Bio

Clinical Focus


  • Neonatal-Perinatal Medicine

Academic Appointments


Honors & Awards


  • Ogden C Bruton Award, Uniformed Services (1972, 1973)
  • Established Investigator, American Heart Association (1979-1984)
  • Distinguished Alumnus Award, Boston University School of Medicine (1996)
  • Honorary Doctor of Medicine, University of Uppsala, Sweden (2004)

Professional Education


  • Board Certification: Pediatrics, American Board of Pediatrics (1971)
  • Medical Education:Boston University School of Medicine (1966) MA
  • Board Certification: Neonatal-Perinatal Medicine, American Board of Pediatrics (1975)
  • Fellowship:UCSF Medical Center (1975) CA
  • Residency:Johns Hopkins University (1969) MD
  • Internship:Johns Hopkins University (1967) MD
  • BA, Yale University, Social Sciences (1962)
  • MD, Boston University, Medicine (1966)

Research & Scholarship

Current Research and Scholarly Interests


Our research program focuses on lung growth and development, and the adverse impact of prolonged mechanical ventilation on the incompletely formed lung, which in very premature infants often leads to a life-threatening condition that was first described as bronchopulmonary dysplasia (Northway WH Jr et al, Stanford University, New Engl J Med 276: 357-368, 1967). This form of neonatal chronic lung disease is the leading cause of long-term hospitalization and recurrent respiratory disorders seen in tiny infants who have been born at less than 28 weeks of gestation. Failed alveolar formation and excess, disordered lung elastin are prominent histological features of this disease, which in some ways resembles adult emphysema. We study the effects of mechanical ventilation, with either air or 40% O2, on genes and proteins that regulate lung growth and development in newborn mice, whose alveoli and pulmonary capillaries form mainly after birth at term gestation. As elastin plays a crucial role in lung growth and development (elastin-null mice die soon after birth from cardiorespiratory failure related to defective alveolar and lung vascular formation), we are especially interested in studying the effects of prolonged mechanical ventilation (cyclic lung stretch) with O2-rich gas (which is often needed to sustain life of extremely premature infants) on genes that regulate elastin synthesis and assembly, which in turn can affect lung septation and angiogenesis. We currently study the effects of lengthy mechanical ventilation on lungs of mutant newborn mice that have defects in elastin assembly and associated abnormalities of lung structure. Because mechanical ventilation of the developing lung can induce the release of proteolytic enzymes that break down elastin, we recently began to study the effects of mechanical ventilation with O2-rich gas in a transgenic mouse that over-expresses elafin, a potent inhibitor of serine elastase activity. We think that these studies will pave the way for novel and effective strategies to treat or prevent neonatal chronic lung disease, and perhaps other respiratory disorders that exhibit similar pathological features in older children and adults.

Teaching

2013-14 Courses


Publications

Journal Articles


  • Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Hilgendorff, A., Parai, K., Ertsey, R., Rey-Parra, G. J., Thebaud, B., Tamosiuniene, R., Jain, N., Navarro, E. F., Starcher, B. C., Nicolls, M. R., Rabinovitch, M., Bland, R. D. 2012; 303 (3): L215-L227
  • Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Hilgendorff, A., Parai, K., Ertsey, R., Jain, N., Navarro, E. F., Peterson, J. L., Tamosiuniene, R., Nicolls, M. R., Starcher, B. C., Rabinovitch, M., Bland, R. D. 2011; 184 (5): 537-546

    Abstract

    Mechanical ventilation with O?-rich gas (MV-O?) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-? activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease.To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O?-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest.Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O? for 8-24 hours; control animals breathed 40% O? without MV. At study's end, lungs were harvested to assess key variables noted below.MV-O? of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-? activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O?-induced changes.Intratracheal elafin, by blocking lung protease activity, prevented MV-O?-induced elastin degradation, TGF-? activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O?. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O? and might be targeted therapeutically to prevent MV-O?-induced lung injury.

    View details for DOI 10.1164/rccm.201012-2010OC

    View details for Web of Science ID 000294478200014

    View details for PubMedID 21562133

  • Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Mokres, L. M., Parai, K., Hilgendorff, A., Ertsey, R., Alvira, C. M., Rabinovitch, M., Bland, R. D. 2010; 298 (1): L23-L35

    Abstract

    Defective lung septation and angiogenesis, quintessential features of neonatal chronic lung disease (CLD), typically result from lengthy exposure of developing lungs to mechanical ventilation (MV) and hyperoxia. Previous studies showed fewer alveoli and microvessels, with reduced VEGF and increased transforming growth factor-beta (TGFbeta) signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs. normal controls. MV of newborn mice with 40% O(2) for 24 h yielded similar lung structural abnormalities linked to impaired VEGF signaling, dysregulated elastin production, and increased apoptosis. These studies could not determine the relative importance of cyclic stretch vs. hyperoxia in causing these lung growth abnormalities. We therefore studied the impact of MV for 24 h with air on alveolar septation (quantitative lung histology), angiogenesis [CD31 quantitative-immunohistochemistry (IHC), immunoblots], apoptosis [TdT-mediated dUTP nick end labeling (TUNEL), active caspase-3 assays], VEGF signaling [VEGF-A, VEGF receptor 1 (VEGF-R1), VEGF-R2 immunoblots], TGFbeta activation [phosphorylated Smad2 (pSmad2) quantitative-IHC], and elastin production (tropoelastin immunoblots, quantitative image analysis of Hart's stained sections) in lungs of 6-day-old mice. Compared with unventilated controls, MV caused a 3-fold increase in alveolar area, approximately 50% reduction in alveolar number and endothelial surface area, >5-fold increase in apoptosis, >50% decrease in lung VEGF-R2 protein, 4-fold increase of pSmad2 protein, and >50% increase in lung elastin, which was distributed throughout alveolar walls rather than at septal tips. This study is the first to show that prolonged MV of developing lungs, without associated hyperoxia, can inhibit alveolar septation and angiogenesis and increase apoptosis and lung elastin, findings that could reflect stretch-induced changes in VEGF and TGFbeta signaling, as reported in CLD.

    View details for DOI 10.1152/ajplung.00251.2009

    View details for Web of Science ID 000272827900005

    View details for PubMedID 19854954

  • Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice Am J Physiol Lung Cell Mol Physiol Bland, R., Ertsey R, Mokres LM, Xu L, Jacobson BE, Jiang S, Alvira CM, Rabinovitch M, Shinwell ES, Dixit A 2008; 294 (1): L3-L14
  • Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Bland, R. D., Mokres, L. M., Ertsey, R., Jacobson, B. E., Jiang, S., Rabinovitch, M., Xu, L., Shinwell, E. S., Zhang, F., Beasley, M. A. 2007; 293 (5): L1099-L1110

    Abstract

    Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: , 2007. First published August 17, 2007; - Mechanical ventilation (MV) with O(2)-rich gas offers life-saving treatment for extremely premature infants with respiratory failure but often leads to neonatal chronic lung disease (CLD), characterized by defective formation of alveoli and blood vessels in the developing lung. We discovered that MV of 2- to 4-day-old mice with 40% O(2) for 8 h, compared with unventilated control pups, reduced lung expression of genes that regulate lung septation and angiogenesis (VEGF-A and its receptor, VEGF-R2; PDGF-A; and tenascin-C). MV with air for 8 h yielded similar results for PDGF-A and tenascin-C but did not alter lung mRNA expression of VEGF or VEGF-R2. MV of 4- to 6-day-old mice with 40% O(2) for 24 h reduced lung protein abundance of VEGF-A, VEGF-R2, PDGF-A, and tenascin-C and resulted in lung structural abnormalities consistent with evolving CLD. After MV with 40% O(2) for 24 h, lung volume was similar to unventilated controls, whereas distal air space size, assessed morphometrically, was greater in lungs of ventilated pups, indicative of impaired septation. Immunostaining for vimentin, which is expressed in myofibroblasts, was reduced in distal lung after 24 h of MV with 40% O(2). These molecular, cellular, and structural changes occurred without detectable lung inflammation as evaluated by histology and assays for proinflammatory cytokines, myeloperoxidase activity, and water content in lung. Thus lengthy MV of newborn mice with O(2)-rich gas reduces lung expression of genes and proteins that are critical for normal lung growth and development. These changes yielded lung structural defects similar to those observed in evolving CLD.

    View details for DOI 10.1152/ajplung.00217.2007

    View details for Web of Science ID 000250870700003

    View details for PubMedID 17704187

  • Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic lung disease AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Bland, R. D., Xu, L., Ertsey, R., Rabinovitch, M., Albertine, K. H., Wynn, K. A., Kumar, V. H., Ryan, R. M., Swartz, D. D., Csiszar, K., Fong, K. S. 2007; 292 (6): L1370-L1384

    Abstract

    Failed alveolar formation and excess, disordered elastin are key features of neonatal chronic lung disease (CLD). We previously found fewer alveoli and more elastin in lungs of preterm compared with term lambs that had mechanical ventilation (MV) with O(2)-rich gas for 3 wk (MV-3 wk). We hypothesized that, in preterm more than in term lambs, MV-3 wk would reduce lung expression of growth factors that regulate alveolarization (VEGF, PDGF-A) and increase lung expression of growth factors [transforming growth factor (TGF)-alpha, TGF-beta(1)] and matrix molecules (tropoelastin, fibrillin-1, fibulin-5, lysyl oxidases) that regulate elastin synthesis and assembly. We measured lung expression of these genes in preterm and term lambs after MV for 1 day, 3 days, or 3 wk, and in fetal controls. Lung mRNA for VEGF, PDGF-A, and their receptors (VEGF-R2, PDGF-Ralpha) decreased in preterm and term lambs after MV-3 wk, with reduced lung content of the relevant proteins in preterm lambs with CLD. TGF-alpha and TGF-beta(1) expression increased only in lungs of preterm lambs. Tropoelastin mRNA increased more with MV of preterm than term lambs, and expression levels remained high in lambs with CLD. In contrast, fibrillin-1 and lysyl oxidase-like-1 mRNA increased transiently, and lung abundance of other elastin-assembly genes/proteins was unchanged (fibulin-5) or reduced (lysyl oxidase) in preterm lambs with CLD. Thus MV-3 wk reduces lung expression of growth factors that regulate alveolarization and differentially alters expression of growth factors and matrix proteins that regulate elastin assembly. These changes, coupled with increased lung elastase activity measured in preterm lambs after MV for 1-3 days, likely contribute to CLD.

    View details for DOI 10.1152/ajplung.00367.2006

    View details for Web of Science ID 000247935700006

    View details for PubMedID 17293375

  • Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs Am J Respir Crit Care Med Bland RD, Albertine KH, Carlton DP, MacRitchie AN 2005; 172 (7): 899-906
  • Neonatal chronic lung disease in the post-surfactant era. Biology of the neonate Bland, R. D. 2005; 88 (3): 181-191

    Abstract

    This is a brief review of neonatal chronic lung disease, sometimes called the 'new bronchopulmonary dysplasia (BPD)'. The clinical, radiographic and pathological features of this condition have changed considerably in recent years because of major advances in perinatal care, including widespread use of antenatal glucocorticoid therapy, postnatal surfactant replacement and improved respiratory and nutritional support. Authentic animal models, featuring lengthy mechanical ventilation of surfactant-treated, premature neonatal baboons and lambs, have provided important insights on the pathophysiology and treatment of this disease. Lung histopathology after 2-4 weeks of positive-pressure ventilation with oxygen-rich gas results in failed formation of alveoli and lung capillaries, excess disordered elastin accumulation, smooth muscle overgrowth in small pulmonary arteries and airways, chronic inflammation and interstitial edema. Treatment interventions that have been tested in these animal models include nasal application of continuous positive airway pressure, high-frequency mechanical ventilation, inhaled nitric oxide and retinol. The challenge now is to improve understanding of the molecular mechanisms that regulate normal lung growth and development, and to clarify the dysregulation of lung structure and function that occurs with injury and subsequent repair so that effective treatment or prevention strategies can be devised and implemented.

    View details for PubMedID 16210840

  • Pulmonary vascular dysfunction in preterm lambs with chronic lung disease AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Bland, R. D., Ling, C. Y., Albertine, K. H., Carlton, D. P., MacRitchie, A. J., Day, R. W., Dahl, M. J. 2003; 285 (1): L76-L85

    Abstract

    Chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and leads to structural abnormalities of the lung circulation in newborn sheep. Compared with normal lambs born at term, chronically ventilated preterm lambs have increased pulmonary arterial smooth muscle and elastin, fewer lung microvessels, and reduced abundance of endothelial nitric oxide synthase. These abnormalities may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). Nitric oxide inhalation (iNO) reduces PVR in human infants and lambs with persistent pulmonary hypertension. We wondered whether iNO might have a similar effect in lambs with CLD. We therefore studied the effect of iNO on PVR in lambs that were delivered prematurely at approximately 125 days of gestation (term = 147 days) and mechanically ventilated for 3 wk. All of the lambs had chronically implanted catheters for measurement of pulmonary vascular pressures and blood flow. During week 2 of mechanical ventilation, iNO at 15 parts/million for 1 h decreased PVR by approximately 20% in 12 lambs with evolving CLD. When the same study was repeated in eight lambs at the end of week 3, iNO had no significant effect on PVR. To see whether this loss of iNO effect on PVR might reflect dysfunction of lung vascular smooth muscle, we infused 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP; 150 microg. kg(-1). min(-1) iv) for 15-30 min in four of these lambs at the end of week 3. PVR consistently decreased by 30-35%. Lung immunohistochemistry and immunoblot analysis of excised pulmonary arteries from lambs with CLD, compared with control term lambs, showed decreased soluble guanylate cyclase (sGC). These results suggest that loss of pulmonary vascular responsiveness to iNO in preterm lambs with CLD results from impaired signaling, possibly related to deficient or defective activation of sGC, the intermediary enzyme through which iNO induces increased vascular smooth muscle cell cGMP and resultant vasodilation.

    View details for DOI 10.1152/ajplung.00395.2002

    View details for Web of Science ID 000183314400009

    View details for PubMedID 12626336

  • Reduced endothelial nitric oxide synthase in lungs of chronically ventilated preterm lambs AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY MacRitchie, A. N., Albertine, K. H., Sun, J. C., Lei, P. S., Jensen, S. C., Freestone, A. A., Clair, P. M., Dahl, M. J., Godfrey, E. A., Carlton, D. P., Bland, R. D. 2001; 281 (4): L1011-L1020

    Abstract

    Nitric oxide (NO), produced in lung vascular endothelium and airway epithelium, has an important role in regulating smooth muscle cell growth and tone. Chronic lung disease, a frequent complication of premature birth, is characterized by excess abundance, tone, and reactivity of smooth muscle in the pulmonary circulation and conducting airways, leading to increased lung vascular and airway resistance. Whether these structural and functional changes are associated with diminished pulmonary expression of endothelial nitric oxide synthase (eNOS) protein is unknown. Both quantitative immunoblot analysis and semiquantitative immunohistochemistry showed that there was less eNOS protein in the endothelium of small intrapulmonary arteries and epithelium of small airways of preterm lambs that were mechanically ventilated for 3 wk compared with control lambs born at term. No significant differences were detected for other proteins (inducible NOS, alpha-smooth muscle actin, and pancytokeratin). Lung vascular and respiratory tract resistances were greater in the chronically ventilated preterm lambs compared with control term lambs. These results support the notion that decreased eNOS in the pulmonary circulation and respiratory tract of preterm lambs may contribute to the pathophysiology of chronic lung disease.

    View details for Web of Science ID 000171020400028

    View details for PubMedID 11557605

  • Chronic lung injury in preterm lambs: Abnormalities of the pulmonary circulation and lung fluid balance PEDIATRIC RESEARCH Bland, R. D., Albertine, K. H., Carlton, D. P., Kullama, L., Davis, P., Cho, S. C., Kim, B. I., DAHL, M., Tabatabaei, N. 2000; 48 (1): 64-74

    Abstract

    Chronic lung disease of early infancy, or bronchopulmonary dysplasia, is a frequent complication of prolonged mechanical ventilation after premature birth. Pulmonary hypertension and edema are common features of this condition, which is often attributed to long-term, repetitive overinflation of incompletely developed lungs. The overall objective of this work was to examine the effects on the pulmonary circulation and lung fluid balance of different ventilation strategies using large versus small inflation volumes in an animal model of bronchopulmonary dysplasia. We studied 16 newborn lambs that were delivered prematurely (124+/-3 d gestation, term = 147 d) by cesarean section and mechanically ventilated for 3 to 4 wk. Ten lambs were ventilated at 20 breaths/min, yielding a tidal volume of 15+/-5 mL/kg, and six lambs were ventilated at 60 breaths/min, yielding a tidal volume of 6+/-2 mL/kg. All lambs received surfactant at birth and had subsequent surgery for closure of the ductus arteriosus and catheter placement to allow serial measurements of pulmonary vascular resistance and lung lymph flow. Chronic lung injury, documented by serial chest radiographs and postmortem pathologic examination, developed in all lambs irrespective of the pattern of assisted ventilation. Pulmonary vascular resistance, which normally decreases during the month after birth at term, did not change significantly from the first to the last week of study. Lung lymph flow, an index of net transvascular fluid filtration, increased with time in lambs that were ventilated at 20 breaths/min, but not in lambs ventilated at 60 breaths/min. Lymph protein concentration decreased with time, indicative of increased fluid filtration pressure, without evidence of a change in lung vascular protein permeability. Postmortem studies showed interstitial lung edema, increased pulmonary arteriolar smooth muscle and elastin, decreased numbers of small pulmonary arteries and veins, and decreased capillary surface density in distal lung of chronically ventilated lambs compared with control lambs that were killed either 1 d (same postconceptional age) or 3 wk (same postnatal age) after birth at term. Thus, chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance and leads to lung edema from increased fluid filtration pressure. These abnormalities of the pulmonary circulation may contribute to the abnormal respiratory gas exchange that often exists in infants with bronchopulmonary dysplasia.

    View details for Web of Science ID 000087882000013

    View details for PubMedID 10879802

  • Chronic lung injury in preterm lambs - Disordered respiratory tract development AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Albertine, K. H., Jones, C. P., Starcher, B. C., Bohnsack, J. F., Davis, P. L., Cho, S. C., Carlton, D. P., Bland, R. D. 1999; 159 (3): 945-958

    Abstract

    The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.

    View details for Web of Science ID 000079106600041

    View details for PubMedID 10051278

  • Chronic lung injury in preterm lambs: Disordered pulmonary elastin deposition AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Pierce, R. A., Albertine, K. H., Starcher, B. C., Bohnsack, J. F., Carlton, D. P., Bland, R. D. 1997; 272 (3): L452-L460

    Abstract

    Prolonged mechanical ventilation of premature neonates is often associated with abnormal morphological development of the lung and chronic lung disease, sometimes called bronchopulmonary dysplasia (BPD). Impaired alveolar development is a hallmark of this disease. To better understand the effects of mechanical ventilation on lung elastin expression, we studied lung tissue from 10 preterm lambs (gestation = 125 days; term = 148 days) mechanically ventilated for 3-4 wk at a respirator rate of 20 breaths/min and tidal volume of 15 +/- 5 ml/kg (n = 5) or 60 breaths/min and tidal volume of 5 +/- 2 ml/kg (n = 5). Histopathology showed increased elastin accumulation and abnormal morphological development in the ventilated groups. Postmortem lung desmosine content was increased significantly in the 20 breaths/min group. Tropoelastin mRNA expression was increased in both ventilated groups. In situ hybridization localized increased tropoelastin mRNA expression to sites of accumulated elastin in extended alveolar walls with scant, attenuated secondary crests. Lung collagen content, as assessed by the amount of hydroxyproline in lung tissue, was similar to controls. These data suggest that excessive production and accumulation of elastin is associated with chronic lung injury from prolonged mechanical ventilation after premature birth.

    View details for Web of Science ID A1997WN86400011

    View details for PubMedID 9124602

  • Molecular determinants of lung development. Annals of the American Thoracic Society Morrisey, E. E., Cardoso, W. V., Lane, R. H., Rabinovitch, M., Abman, S. H., Ai, X., Albertine, K. H., Bland, R. D., Chapman, H. A., Checkley, W., Epstein, J. A., Kintner, C. R., Kumar, M., Minoo, P., Mariani, T. J., McDonald, D. M., Mukouyama, Y., Prince, L. S., Reese, J., Rossant, J., Shi, W., Sun, X., Werb, Z., Whitsett, J. A., Gail, D., Blaisdell, C. J., Lin, Q. S. 2013; 10 (2): S12-6

    Abstract

    Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.

    View details for DOI 10.1513/AnnalsATS.201207-036OT

    View details for PubMedID 23607856

  • Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Albertine, K. H., Dahl, M. J., Gonzales, L. W., Wang, Z., Metcalfe, D., Hyde, D. M., Plopper, C. G., Starcher, B. C., Carlton, D. P., Bland, R. D. 2010; 299 (1): L59-L72

    Abstract

    Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O(2)-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term approximately 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.

    View details for DOI 10.1152/ajplung.00380.2009

    View details for Web of Science ID 000281388900008

    View details for PubMedID 20382748

  • Blunted hypoxic pulmonary vasoconstriction in experimental neonatal chronic lung disease AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rey-Parra, G. J., Archer, S. L., Bland, R. D., Albertine, K. H., Carlton, D. P., Cho, S., Kirby, B., Haromy, A., Eaton, F., Wu, X., Thebaud, B. 2008; 178 (4): 399-406

    Abstract

    Neonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O(2)-rich gas, is the most common cause of long-term hospitalization and recurrent respiratory illness in extremely premature infants. Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening CLD. The mechanism that causes these hypoxemic episodes is unknown. Hypoxic pulmonary vasoconstriction (HPV), which is partially controlled by O(2)-sensitive voltage-gated potassium (K(v)) channels, is an important adaptive response to local hypoxia that helps to match perfusion and ventilation in the lung.To test the hypothesis that chronic lung injury (CLI) impairs HPV.We studied preterm lambs that had MV with O(2)-rich gas for 3 weeks and newborn rats that breathed 95%-O(2) for 2 weeks, both of which resulted in airspace enlargement and pulmonary vascular changes consistent with CLD.HPV was attenuated in preterm lambs with CLI after 2 weeks of MV and in newborn rats with CLI after 2 weeks of hyperoxia. HPV and constriction to the K(v)1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K(v)1.5 and K(v)2.1 mRNA and K(+) current. Intrapulmonary gene transfer of K(v)1.5, encoding the ion channel that is thought to trigger HPV, increased O(2)-sensitive K(+) current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats.Reduced expression/activity of O(2)-sensitive K(v) channels in dPAs contributes to blunted HPV observed in neonatal CLD.

    View details for DOI 10.1164/rccm.200711-1631OC

    View details for Web of Science ID 000258678600013

    View details for PubMedID 18511704

  • Impaired alveolar development and abnormal lung elastin in preterm lambs with chronic lung injury: Potential benefits of retinol treatment BIOLOGY OF THE NEONATE Bland, R. D., Albertine, K. H., Pierce, R. A., Starcher, B. C., Carlton, D. P. 2003; 84 (1): 101-102

    View details for DOI 10.1159/000071012

    View details for Web of Science ID 000184493100016

    View details for PubMedID 12890945

  • Loss of liquid from the lung lumen in labor: more than a simple "squeeze" AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Bland, R. D. 2001; 280 (4): L602-L605

    View details for Web of Science ID 000167357200006

    View details for PubMedID 11237999

  • Inhaled nitric oxide: A premature remedy for chronic lung disease? PEDIATRICS Bland, R. D. 1999; 103 (3): 667-670

    View details for Web of Science ID 000078960100035

    View details for PubMedID 10049974

  • Altered vascular development in preterm lambs with chronic lung injury CHEST Albertine, K. H., MacRitchie, A. N., Young, B. J., Cho, S. C., Kullama, L. K., Carlton, D. P., Bland, R. D. 1998; 114 (1): 6S-7S

    View details for Web of Science ID 000074906100004

    View details for PubMedID 9676601

  • Role of neutrophils in lung vascular injury and edema after premature birth in lambs JOURNAL OF APPLIED PHYSIOLOGY Carlton, D. P., Albertine, K. H., Cho, S. C., LONT, M., Bland, R. D. 1997; 83 (4): 1307-1317

    Abstract

    To investigate the role of neutrophils in the pathogenesis of respiratory distress after premature birth, we assessed the relationship between circulating neutrophil concentration and neutrophil accumulation in the lung, lung lymph and pleural liquid flow, and extravascular lung water in 10 chronically catheterized preterm lambs (127 +/- 1 days gestation) that were mechanically ventilated for 8 h after birth. Circulating neutrophil concentration transiently decreased within 2 h after birth and then returned to prenatal values by 6-8 h. The decrease in circulating neutrophil concentration was related directly to the accumulation of neutrophils in the air spaces, drainage of liquid and protein from the lung 6-8 h after delivery, and postmortem extravascular lung water. In additional studies, we intravenously administered mechlorethamine to 5 fetal lambs to reduce circulating neutrophils before delivery (neutrophil concentration before birth: 9 +/- 11 cells/microl). Compared with control lambs, neutrophil-depleted lambs had significantly less drainage of liquid (7.8 +/- 5.9 vs. 2.6 +/- 1.9 ml/h, respectively) and protein (116 +/- 74 vs. 42 +/- 27 mg/h, respectively) from the lung 6-8 h after birth and significantly less extravascular lung water at postmortem (6.5 +/- 0. 8 vs. 4.8 0.6 g/g dry lung, respectively). Thus neutrophils contribute to the pathogenesis of respiratory distress after premature birth by increasing lung vascular protein permeability and promoting lung edema.

    View details for Web of Science ID A1997XZ83500034

    View details for PubMedID 9338441

  • VASOPRESSIN EFFECTS ON LUNG LIQUID VOLUME IN FETAL SHEEP PEDIATRIC RESEARCH Cummings, J. J., Carlton, D. P., Poulain, F. R., Fike, C. D., Keil, L. C., Bland, R. D. 1995; 38 (1): 30-35

    Abstract

    The normal switch from placental to pulmonary gas exchange at birth requires rapid removal of liquid from the lungs. Previous reports contend that vasopressin may be important in regulating this process, but this notion derives from studies in which fetal sheep received very large doses of vasopressin that yielded plasma concentrations at least 10 times greater than those that have been measured during normal labor. To study the physiologic effects of vasopressin on lung liquid volume in fetal sheep, we made three sets of experiments. First, we measured plasma vasopressin concentrations [VP] in 15 late-gestation fetal sheep, five of which were at various stages of spontaneous labor. [VP] in these fetuses ranged from < 1 (prelabor) to 31 (during labor) microU/mL; postmortem extravascular lung water (EVLW) ranged from 4.5 to 14.5 g/g dry lung tissue. In a second series of studies, we measured EVLW in five sets of near-term (138 +/- 1 d, term = 147 d) twin fetal sheep that received an 8-h i.v. infusion of either isotonic saline (control twin) or AVP (AVP-treated twin) at a rate of approximately 1 (mU/kg)/min. This dose was chosen to mimic [VP] measured in fetuses that had been studied during labor. [VP] did not change in the control twins, whereas [VP] increased from 1.8 +/- 1.0 to 27.7 +/- 3.5 microU/mL in treated twins. There was a small, statistically significant difference in EVLW between twins that received AVP and untreated twins (11.9 +/- 1.8 versus 14.6 +/- 2.8 g/g dry lung).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995RF13000006

    View details for PubMedID 7478793

  • RETROVIRUS-MEDIATED GENE-TRANSFER IN LUNGS OF LIVING FETAL SHEEP GENE THERAPY Pitt, B. R., Schwarz, M. A., Pilewski, J. M., Nakayama, D., Mueller, G. M., Robbins, P. D., Watkins, S. A., Albertine, K. H., Bland, R. D. 1995; 2 (5): 344-350

    Abstract

    In utero somatic gene transfer may be a useful therapeutic strategy for a variety of inherited disorders. In the present study, we demonstrate transgene expression in the airways of fetal lamb lungs, 2-3 weeks after injection of Moloney murine leukemia retrovirus based vectors containing cDNA for beta-galactosidase (lacZ) or human interleukin receptor antagonist protein (IRAP), into the fluid filled future airspace of fully catheterized twin fetal lambs (104-117 days gestational age; term 147 days). Expression of lacZ or IRAP was limited to the twin that received the respective vector and was apparent, at light microscopic level, in the epithelium and submucosal space of proximal airways, and to a lesser extent, in the respiratory epithelium of the distal airways. These data demonstrate for the first time that transfer of foreign DNA to fetal lung can be accomplished. These findings support the use of retroviral vectors for somatic lung DNA transfer and suggest that inherited disorders such as cystic fibrosis may be approached therapeutically via gene transfer, in utero.

    View details for Web of Science ID A1995RH47000007

    View details for PubMedID 7671110

  • SURFACTANT TREATMENT AT BIRTH REDUCES LUNG VASCULAR INJURY AND EDEMA IN PRETERM LAMBS PEDIATRIC RESEARCH Carlton, D. P., Cho, S. C., Davis, P., LONT, M., Bland, R. D. 1995; 37 (3): 265-270

    Abstract

    To study the effect of surfactant administration on fluid balance in the premature lung, we measured pulmonary vascular pressures, lung lymph and pleural liquid flow, and concentrations of protein in lymph, pleural liquid, and plasma before and after birth in 12 chronically catheterized preterm lambs (127-128 d gestation) treated with either placebo or surfactant just before surgical delivery. Eight lambs received intrapulmonary saline (placebo), and four lambs received surfactant; all lambs were mechanically ventilated with O2 for 8 h after birth. In control lambs, lung lymph and pleural liquid flow increased from 2.7 +/- 0.4 mL/h during the 2-4 h before birth to 9.2 +/- 2.1 mL/h by 6-8 h after birth; lymph and pleural space protein drainage increased from 58 +/- 7 mg/h during the 2-4 h before birth to 134 +/- 25 mg/h by 6-8 h after birth. In lambs treated with surfactant, there was no significant increase in lymph and pleural liquid flow after birth (before birth, 2.3 +/- 0.3 mL/h; 6-8 h after birth, 3.4 +/- 0.9 mL/h); likewise, lymph and pleural space protein drainage did not change after birth (before birth, 54 +/- 6 mg/h; 6-8 h after birth, 50 +/- 8 mg/h). Postmortem extravascular lung water was significantly less in lambs treated with surfactant compared with control lambs (control, 6.5 +/- 0.3 g/g dry lung; surfactant-treated, 5.0 +/- 0.2 g/g dry lung).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995QJ99700003

    View details for PubMedID 7784133

  • LUNG VASCULAR PROTEIN PERMEABILITY IN PRETERM FETAL AND MATURE NEWBORN SHEEP JOURNAL OF APPLIED PHYSIOLOGY Carlton, D. P., Cummings, J. J., SCHEERER, R. G., Bland, R. D. 1994; 77 (2): 782-788

    Abstract

    The purpose of this study was to see whether there are developmental differences in the protein permeability of the pulmonary circulation that might contribute to the abnormal lung fluid balance seen in premature lambs with respiratory failure. In one series of experiments, we measured albumin turnover time, which reflects the escape rate of radiolabeled albumin from the pulmonary circulation, of five preterm fetal lambs (125 +/- 1 days gestation) and five newborn lambs (19 +/- 9 days old). Turnover time was not significantly different in fetuses (160 +/- 38 min) and newborns (141 +/- 54 min), implying a similar protein permeability of the pulmonary circulation. In additional experiments, we measured pulmonary hemodynamic and lung lymph flow responses to intravenous saline infusion in seven preterm fetal lambs (130 +/- 3 days gestation) and seven newborn lambs (14 +/- 3 days old). During saline infusion, calculated fluid filtration pressure increased by a similar amount in fetuses and newborns (3.4 +/- 0.8 and 2.8 +/- 0.9 Torr, respectively), resulting in a similar change in lung lymph flow in fetuses and newborns (0.59 +/- 0.27 and 0.55 +/- 0.25 ml.h-1.kg body wt-1, respectively). The results of these studies indicate that protein permeability of the pulmonary circulation does not change significantly during late fetal and early postnatal development.

    View details for Web of Science ID A1994PB78700039

    View details for PubMedID 8002528

  • Inflation pressure and lung vascular injury in preterm lambs. Chest Carlton, D. P., Cho, S. C., Davis, P., Bland, R. D. 1994; 105 (3): 115S-116S

    View details for PubMedID 8131601

  • CHANGES IN LUNG LIQUID DURING SPONTANEOUS LABOR IN FETAL SHEEP JOURNAL OF APPLIED PHYSIOLOGY Chapman, D. L., Carlton, D. P., Nielson, D. W., Cummings, J. J., Poulain, F. R., Bland, R. D. 1994; 76 (2): 523-530

    Abstract

    The goals of this study were 1) to examine changes in lung liquid formation and composition during spontaneous labor in fetal lambs and 2) to determine the importance of beta-adrenergic stimulation and transepithelial Na+ flux in removing liquid from the lung lumen near birth. We measured net production of lung liquid (Jv), lung liquid composition, and transpulmonary electrical potential difference (PD) before and during labor in fetal sheep with chronically implanted tracheal and vascular catheters. We determined Jv by measuring rate of change in lung liquid concentration of 125I-albumin, an impermeant tracer that was mixed in lung liquid at the start of each study. In 17 paired experiments, Jv decreased from 11 +/- 2 ml/h (Jv > 0 = secretion) before labor to -1 +/- 2 ml/h (Jv < 0 = absorption) during labor; in 5 paired experiments, PD changed from -7 +/- 1 mV (lumen negative) before labor to -12 +/- 1 mV during labor. To determine whether absorption of lung liquid during labor is the result of beta-adrenergic stimulation, we studied the effect of propranolol on Jv during labor. When propranolol (40 microM) was added to lung liquid during active labor, Jv decreased from -2 +/- 2 to -8 +/- 3 ml/h (n = 9). Thus, propranolol did not inhibit lung liquid absorption during labor. To determine whether transepithelial Na+ movement provides the driving force for lung liquid clearance during labor, we tested the effects of amiloride, an Na+ transport inhibitor, on Jv and PD.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994MX61000005

    View details for PubMedID 8175558

  • HYPOPROTEINEMIA SLOWS LUNG LIQUID CLEARANCE IN YOUNG LAMBS JOURNAL OF APPLIED PHYSIOLOGY Cummings, J. J., Carlton, D. P., Poulain, F. R., Raj, J. U., Bland, R. D. 1993; 74 (1): 153-160

    Abstract

    To determine whether hypoproteinemia slows the rate at which liquid is cleared from the lung lumen, we studied 36 lambs, 18 of which underwent repeated plasmapheresis, reducing plasma protein concentration by 37% and plasma protein osmotic pressure by 39%. We killed 29 lambs (14 hypoproteinemic and 15 normoproteinemic) and removed their lungs 1, 2, or 6 h after intratracheal instillation of isotonic saline (6 ml/kg body wt). We measured extravascular lung water and determined the percentage of tracheally instilled liquid that was cleared from the lungs by comparison with control lambs that did not receive saline into their airways. The percent liquid cleared from the lungs after 1 and 2 h was significantly less in hypoproteinemic than in normoproteinemic lambs (37 vs. 65% at 1 h, 58 vs. 75% at 2 h, respectively). By 6 h nearly all the liquid (> 92%) was cleared from the lungs of all lambs. Thus hypoproteinemia slows the initial rate of clearance of liquid from the lungs of lambs. To determine whether reduced plasma protein osmotic pressure might redirect this liquid into lung lymphatics, we measured lung lymph flow (Q1) in five lambs (7.7 +/- 1.4 kg, 19 +/- 4 days old) for > or = 2 h before and 6 h after tracheal instillation of saline. In each lamb, paired studies were done 3-6 days apart; between studies the lambs underwent plasmapheresis.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993KJ48000020

    View details for PubMedID 8444686

  • INCREASED PULMONARY VASCULAR FILTRATION PRESSURE DOES NOT ALTER LUNG LIQUID SECRETION IN FETAL SHEEP JOURNAL OF APPLIED PHYSIOLOGY Carlton, D. P., Cummings, J. J., Poulain, F. R., Bland, R. D. 1992; 72 (2): 650-655

    Abstract

    The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.

    View details for Web of Science ID A1992HE26800036

    View details for PubMedID 1559944

  • ION-TRANSPORT REGULATION OF LUNG LIQUID SECRETION IN FETAL LAMBS JOURNAL OF DEVELOPMENTAL PHYSIOLOGY Carlton, D. P., Cummings, J. J., Chapman, D. L., Poulain, F. R., Bland, R. D. 1992; 17 (2): 99-107

    Abstract

    To test the hypothesis that liquid formation in the foetal lung reflects the balance between Cl- secretion and Na+ absorption by the respiratory tract epithelium, we studied the independent and combined effects of selective ion transport inhibitors on basal production of lung liquid in foetal lambs. We prepared 19 foetal lambs (gestation 125 +/- 4, term = 147 days) with chronic indwelling catheters for subsequent measurement of luminal liquid production over time (JV). Using an impermeant tracer technique, we measured JV before and after tracheal instillation of 2 different inhibitors of ion transport: bumetanide, a Na(+)-K(+)-2Cl- co-transport inhibitor, and amiloride, a Na+ transport inhibitor. In 7 foetuses we sequentially added bumetanide (10(-4) M) and 2 different concentrations of amiloride (10(-6) M, 10(-4) M) to the liquid within the lung lumen. After we gave bumetanide, JV decreased from 12 +/- 4 ml/h to 0 +/- 5 ml/h and subsequently increased during the 2 periods of amiloride exposure (10(-6) M: 6 +/- 5 ml/h; 10(-4) M: 7 +/- 7 ml/h). In 5 control studies we gave bumetanide, followed by only amiloride vehicle. JV for all time periods in the control studies was similar to the experimental group, demonstrating no effect of amiloride. In 5 foetuses we administered the 2 concentrations of amiloride before bumetanide. There was no change in JV with either concentration of amiloride (baseline: 13 +/- 2 ml/h; 10(-6) M amiloride: 15 +/- 5 ml/h; 10(-4) M amiloride: 13 +/- 6 ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992LZ45700007

    View details for PubMedID 1500638

  • DEVELOPMENTAL-CHANGES IN LUNG EPITHELIAL ION-TRANSPORT AND LIQUID MOVEMENT ANNUAL REVIEW OF PHYSIOLOGY Bland, R. D., Nielson, D. W. 1992; 54: 373-394

    Abstract

    During fetal life, the lungs are filled with liquid that flows from the pulmonary circulation across the epithelium in response to the osmotic force generated by Cl- secretion of airway and distal lung epithelial cells. As birth approaches, net Cl- secretion across the respiratory tract epithelium decreases, and this is associated with a reduction in the flow of liquid into the lung lumen. The cause for this change is unknown, but several recent studies indicate that it may be related to alterations in the hormonal milieu to which the lung epithelium is exposed late in gestation. The switch from placental to pulmonary gas exchange at birth requires rapid removal of liquid from the lung lumen. During labor and the immediate postnatal period, the pulmonary epithelium changes from a predominantly Cl-(-)secreting membrane to a predominantly Na(+)-absorbing membrane, with resultant reversal of the direction of flow of lung liquid. There is considerable evidence that this change reflects an active metabolic process involving increased Na(+)-K(+)-ATPase activity in lung epithelial cells, which drives liquid from the lung lumen into the interstitium, with subsequent absorption into the pulmonary circulation. This Na(+)-K(+)-ATPase-dependent process persists in the bronchopulmonary epithelium of the mature lung and probably has an important role in clearance of alveolar edema associated with heart failure or lung injury.

    View details for Web of Science ID A1992HJ05600021

    View details for PubMedID 1314041

  • INTRAPULMONARY TERBUTALINE AND AMINOPHYLLINE DECREASE LUNG LIQUID IN FETAL LAMBS PEDIATRIC RESEARCH Chapman, D. L., Carlton, D. P., Cummings, J. J., Poulain, F. R., Bland, R. D. 1991; 29 (4): 357-361

    Abstract

    To see if phosphodiesterase inhibition might enhance the effect of beta-adrenergic stimulation on fetal lung liquid secretion, we studied the independent and combined effects of intrapulmonary terbutaline and aminophylline on net production of lung luminal liquid over time (Jv) in fetal lambs with chronically placed tracheal loop catheters. We calculated Jv during baseline and experimental periods (90-120 min each) by measuring serial concentrations of 125I-albumin, an impermeant tracer that was well mixed in the luminal liquid. In 21 experiments, tracheal instillation of terbutaline (10(-5) M) decreased Jv from 11 +/- 1 (mean +/- SEM) to -3 +/- 2 mL/h. In six other studies, aminophylline (10(-3) M) alone had no significant effect on Jv. In 12 experiments, we gave the two drugs sequentially: terbutaline decreased Jv from 11 +/- 2 to -3 +/- 2 mL/h and aminophylline further decreased Jv to -8 +/- 2 mL/h. Amiloride (10(-4) M), an inhibitor of epithelial Na+ transport, reversed the combined effect of terbutaline and aminophylline, increasing Jv to 8 +/- 1 mL/h. Thus, phosphodiesterase inhibition enhances the beta-adrenergic effect of terbutaline on Na(+)-dependent absorption of liquid from the lung lumen of fetal lambs.

    View details for Web of Science ID A1991FE03600008

    View details for PubMedID 1852529

  • Pathophysiology of neonatal lung injury. International journal of technology assessment in health care Bland, R. D. 1991; 7: 56-60

    View details for PubMedID 2037439

  • DEVELOPMENTAL-CHANGES IN PLEURAL LIQUID PROTEIN-CONCENTRATION IN SHEEP AMERICAN REVIEW OF RESPIRATORY DISEASE Broaddus, V. C., Araya, M., Carlton, D. P., Bland, R. D. 1991; 143 (1): 38-41

    Abstract

    The source of normal pleural liquid is thought to be the systemic circulation of the pleural membranes rather than the pulmonary circulation of the nearby lung. Evidence for a systemic origin comes from the low protein concentration of pleural liquid in adult sheep, which is consistent with protein sieving from a high-pressure circulation. During normal development from fetal to adult life, systemic vascular pressure increases. We therefore reasoned that if pleural liquid comes from the systemic circulation, pleural liquid protein concentration relative to plasma protein concentration should decrease during normal development. To test this hypothesis we did thoracotomies on 14 fetal, 9 newborn, and 15 adult sheep and collected pleural liquid and plasma for measurement of total protein and albumin concentrations. In separate experiments we measured steady-state systemic and pulmonary vascular pressures in age-matched chronically instrumented fetal, newborn, and adult sheep. The protein concentration in pleural liquid relative to that in plasma (pleural liquid/plasma) decreased progressively with age (fetuses, 0.50 +/- 0.15 [SD]; newborns, 0.27 +/- 0.08; adult, 0.15 +/- 0.05); the trend was similar for pleural liquid/plasma albumin ratios as a function of age. Systemic arterial pressure increased progressively during development, whereas pulmonary arterial pressure decreased from the fetus to the adult sheep. These observations support the hypothesis that normal pleural liquid originates from a systemic circulation.

    View details for Web of Science ID A1991ET18600007

    View details for PubMedID 1986682

  • DEVELOPMENTAL DIFFERENCES IN RABBIT LUNG EPITHELIAL-CELL NA+-K+-ATPASE AMERICAN JOURNAL OF PHYSIOLOGY Chapman, D. L., Widdicombe, J. H., Bland, R. D. 1990; 259 (6): L481-L487

    Abstract

    Previous studies showed that ouabain-sensitive rubidium (86Rb+) uptake by rabbit lung epithelial cells increases at birth, followed by a more gradual postnatal increase, reaching adult values by age 30 days. To see whether these changes in ouabain-sensitive cation transport were the result of changes in Na+ pump number or turnover rate, we measured binding of [3H]ouabain and ouabain-sensitive 86Rb+ uptake by freshly isolated lung epithelial cells harvested from near-term fetal, newborn, and adult rabbits. Ouabain-sensitive 86Rb+ uptake by fetal cells was 1/4 that of newborn cells and 1/10 that of adult cells. The maximal number of ouabain binding sites (Umax) was the same for fetal and newborn cells but almost threefold greater for adult cells. Na+ pump turnover rate, determined from ouabain-sensitive 86Rb+ uptake and Umax, was four times greater in newborn and adult cells than it was in fetal cells. Thus the increase in 86Rb+ uptake at birth could be explained by an increase in Na(+)-K(+)-adenosinetriphosphatase (ATPase) turnover rate, whereas the postnatal increase in 86Rb+ uptake could be accounted for by an increase in the amount of Na(+)-K(+)-ATPase per cell.

    View details for Web of Science ID A1990EQ38200085

    View details for PubMedID 2175558

  • LUNG OVEREXPANSION INCREASES PULMONARY MICROVASCULAR PROTEIN PERMEABILITY IN YOUNG LAMBS JOURNAL OF APPLIED PHYSIOLOGY Carlton, D. P., Cummings, J. J., SCHEERER, R. G., Poulain, F. R., Bland, R. D. 1990; 69 (2): 577-583

    Abstract

    To study the effects of inflation pressure and tidal volume (VT) on protein permeability in the neonatal pulmonary microcirculation, we measured lung vascular pressures, blood flow, lymph flow (QL), and concentrations of protein in lymph (L) and plasma (P) of 22 chronically catheterized lambs that received mechanical ventilation at various peak inflation pressures (PIP) and VT. Nine lambs were ventilated initially with a PIP of 19 +/- 1 cmH2O and a VT of 10 +/- 1 ml/kg for 2-4 h (base line), after which we overexpanded their lungs with a PIP of 58 +/- 3 cmH2O and a VT of 48 +/- 4 ml/kg for 4-8 h. QL increased from 2.1 +/- 0.4 to 13.9 +/- 5.0 ml/h. L/P did not change, but the ratio of albumin to globulin in lymph relative to the same ratio in plasma decreased, indicating altered protein sieving in the pulmonary microcirculation. Seven other lambs were mechanically ventilated for 2-4 h at a PIP of 34 +/- 1 cmH2O and a VT of 23 +/- 2 ml/kg (base line), after which their chest and abdomen were bound so that PIP increased to 54 +/- 1 cmH2O for 4-6 h without a change in VT. QL decreased on average from 2.8 +/- 0.6 to 1.9 +/- 0.3 ml/h (P = 0.08), and L/P was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990DV92200025

    View details for PubMedID 2228868

  • LUNG EPITHELIAL ION-TRANSPORT AND FLUID MOVEMENT DURING THE PERINATAL-PERIOD AMERICAN JOURNAL OF PHYSIOLOGY Bland, R. D. 1990; 259 (2): L30-L37

    Abstract

    During fetal life, the mammalian lung is a secretory organ that serves no respiratory function. Its potential airspaces are filled with liquid that flows from the pulmonary circulation across the epithelium in response to the osmotic force generated by Cl- secretion of airway and distal lung epithelial cells. As birth approaches, net Cl- secretion across the respiratory tract epithelium decreases, and this is associated with a reduction in the flow of liquid into the lung lumen. The cause for this change is unknown, but several recent studies indicate that it may be related to alterations in the hormonal milieu to which the lung epithelium is exposed late in gestation. The switch from placental to pulmonary gas exchange at birth requires rapid removal of liquid from the lung lumen. During labor and the immediate postnatal period, the pulmonary epithelium changes from a predominantly Cl- secreting membrane to a predominantly Na(+)-absorbing membrane, with resultant reversal of the direction of flow of lung liquid. There is considerable evidence that this change reflects an active metabolic process involving increased Na(+)-K(+)-ATPase activity in lung epithelial cells, which drives liquid from the lung lumen into the interstitium, with subsequent absorption into the pulmonary circulation.

    View details for Web of Science ID A1990DU95300073

    View details for PubMedID 2200282

  • FUROSEMIDE REDUCES LUNG FLUID FILTRATION IN LAMBS WITH LUNG MICROVASCULAR INJURY FROM AIR EMBOLI JOURNAL OF APPLIED PHYSIOLOGY BERNER, M. E., Teague, W. G., SCHEERER, R. G., Bland, R. D. 1989; 67 (5): 1990-1996

    Abstract

    To study the effects of furosemide on the neonatal pulmonary circulation in the presence of lung injury, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine lambs that received furosemide, 2 mg/kg iv, during a continuous 8-h intravenous infusion of air. Air embolism increased pulmonary vascular resistance by 71% and nearly tripled steady-state lung lymph flow, with no change in lymph-to-plasma protein ratio. These findings reflect an increase in lung vascular protein permeability. During sustained lung endothelial injury, diuresis from furosemide led to a rapid reduction in cardiac output (average 29%) and a 2-Torr decrease in left atrial pressure. Diuresis also led to hemoconcentration, with a 15% increase in both plasma and lymph protein concentrations. These changes were associated with a 27% reduction in lung lymph flow. In a second set of studies, we prevented the reduction in left atrial pressure after furosemide by inflating a balloon catheter in the left atrium. Nevertheless, lymph flow decreased by 25%, commensurate with the reduction in cardiac output that occurred after furosemide. In a third series of experiments, we minimized the furosemide-related decrease in cardiac output by opening an external fistula between the carotid artery and jugular vein immediately after injection of furosemide. In these studies, the reduction in lung lymph flow (average 17%) paralleled the smaller (17%) decrease in cardiac output. These results suggest that changes in lung vascular filtration pressure probably do not account for the reduction in lung lymph flow after furosemide in the presence of lung vascular injury.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989CB81200038

    View details for PubMedID 2600030

  • LUNG FLUID BALANCE IN LAMBS BEFORE AND AFTER PREMATURE BIRTH JOURNAL OF CLINICAL INVESTIGATION Bland, R. D., Carlton, D. P., SCHEERER, R. G., Cummings, J. J., Chapman, D. L. 1989; 84 (2): 568-576

    Abstract

    The purpose of this study was to see if lung vascular protein permeability is greater in preterm lambs with respiratory distress than it is in lambs without lung disease. We measured pulmonary vascular pressures, lung lymph flow, and concentrations of protein in lymph and plasma of 10 chronically catheterized preterm lambs (gestation 133 +/- 1 d) for 2-4 h before and for 4-8 h after delivery by cesarean section. All lambs were treated with mechanical ventilation after birth and received a constant intravenous infusion of glucose-saline solution at an hourly rate of 10 ml/kg. Respiratory failure developed in six lambs, in which there was a sustained threefold postnatal increase in lung lymph flow and lymph protein flow, with an even greater increase in pleural liquid drainage. Concentrations of protein in lymph and pleural liquid were almost identical, averaging approximately 75% of the plasma protein concentration. In the four preterm lambs without lung disease, lymph flow and lymph protein flow were either near or below fetal values by 6-8 h after birth, and there was little or no pleural liquid drainage. Extravascular lung water averaged 7.3 +/- .8 g/g dry lung in lambs with respiratory failure compared to 4.8 +/- .5 g/g dry lung in lambs without lung disease. Thus, pulmonary edema with abnormal leakage of protein-rich liquid from the lung microcirculation into the interstitium is an important pathological feature of the respiratory disease that often occurs after premature birth.

    View details for Web of Science ID A1989AJ47100025

    View details for PubMedID 2760201

  • EFFECT OF PULMONARY PERFUSION ON LUNG FLUID FILTRATION IN YOUNG LAMBS AMERICAN JOURNAL OF PHYSIOLOGY Teague, W. G., BERNER, M. E., Bland, R. D. 1988; 255 (6): H1336-H1341

    Abstract

    To study the effect of pulmonary perfusion on fluid filtration in the newborn lung, we measured pulmonary vascular pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine healthy, awake lambs, 2-3 wk old, before and during sustained alterations in pulmonary blood flow. A 12% reduction in cardiac output (from partial occlusion of the inferior vena cava) led to a corresponding decrease in lymph flow, consistent with a reduction in net lung fluid filtration. A 20% increase in pulmonary blood flow (from opening an external shunt between the carotid artery and jugular vein) increased lymph flow by approximately 40%, without a significant change in lymph protein concentration. These findings suggest that lung microvascular surface area expanded in response to increased perfusion, with little or no change in filtration pressure. In five lambs, lung microvascular pressure was increased by inflating a balloon catheter in the left atrium to establish full patency of the pulmonary microcirculation. In the presence of left atrial pressure elevation, increased perfusion through the arteriovenous shunt had no significant effect on pulmonary vascular pressures or lymph flow. Thus, in young lambs, modest changes in pulmonary blood flow may affect lung fluid filtration by altering perfused microvascular surface area; this response is inhibited in the presence of left atrial hypertension.

    View details for Web of Science ID A1988R495800011

    View details for PubMedID 3202197

  • MICROVASCULAR PRESSURES DURING HYPOXIA IN ISOLATED LUNGS OF NEWBORN RABBITS JOURNAL OF APPLIED PHYSIOLOGY Fike, C. D., LaiFook, S. J., Bland, R. D. 1988; 65 (1): 283-287

    Abstract

    The purpose of this study was to determine the sites of hypoxic vasoconstriction in lungs of newborn rabbits. We isolated and perfused with blood the lungs from 19 rabbit pups, 7-23 days old. We maintained blood flow constant, continuously monitored pulmonary arterial and left atrial pressures, and alternated ventilation of the lungs with 95% O2-5% CO2 (control), and 95% N2-5% CO2 (hypoxia). Using micropipettes and a servonulling device, we measured pressures in 20-60-micron-diam subpleural arterioles and venules during control and hypoxic conditions. We inflated the lungs to a constant airway pressure of 5-7 cmH2O and kept left atrial pressure greater than airway pressure (zone 3) during micropuncture. In eight lungs we measured microvascular pressures first during control and then during hypoxia. We reversed this order in four lungs. In seven lungs we measured microvascular pressures only during hypoxia. We found a significant increase in pulmonary arterial pressure with no change in microvascular pressures. These results indicate that the site of hypoxic vasoconstriction in lungs of newborn rabbits is arteries greater than 60 micron in diameter.

    View details for Web of Science ID A1988P400100040

    View details for PubMedID 3403470

  • LUNG LIQUID CLEARANCE BEFORE AND AFTER BIRTH SEMINARS IN PERINATOLOGY Bland, R. D. 1988; 12 (2): 124-133

    View details for Web of Science ID A1988N464100005

    View details for PubMedID 3293223

  • ALVEOLAR LIQUID PRESSURES IN NEWBORN AND ADULT-RABBIT LUNGS JOURNAL OF APPLIED PHYSIOLOGY Fike, C. D., LaiFook, S. J., Bland, R. D. 1988; 64 (4): 1629-1635

    Abstract

    To study the effects of lung maturation and inflation on alveolar liquid pressures, we isolated lungs from adult and newborn rabbit pups (1-11 days old). We used the micropuncture technique to measure alveolar liquid pressure at several transpulmonary pressures on lung deflation. Alveolar liquid pressure was greater than pleural pressure but less than airway pressure at all transpulmonary pressures. Alveolar liquid pressure decreased further below airway pressure with lung inflation. At high transpulmonary pressure, alveolar liquid pressure was less in newborn than in adult lungs. To study the effects of edema, we measured alveolar liquid pressures in newborn lungs with different wet-to-dry weight ratios. Alveolar liquid pressure increased with progressive edema. In addition, we compared alveolar liquid and perivenular interstitial pressures in perfused newborn lungs and found that they were similar. Thus alveolar liquid pressure can be used to estimate perivenular interstitial pressure. We conclude that the transvascular pressure gradient for fluid flux into the interstitium might increase with lung inflation and decrease with progressive edema. Furthermore, this gradient might be greater in newborn than adult lungs at high inflation pressures.

    View details for Web of Science ID A1988N072400046

    View details for PubMedID 3378997

  • EFFECT OF HYPOXIA ON LUNG LYMPH-FLOW IN NEWBORN LAMBS WITH LEFT ATRIAL HYPERTENSION AMERICAN JOURNAL OF PHYSIOLOGY Raj, J. U., Hazinski, T. A., Bland, R. D. 1988; 254 (3): H487-H493

    Abstract

    To determine the effect of left atrial hypertension on the vascular response to hypoxia in the newborn lung, we measured pulmonary artery and left atrial pressures, lung blood flow and lymph flow, and concentrations of protein in lymph and plasma of 13 lambs that spontaneously breathed air for 2-6 h (control period), followed by 8-11% O2 mixed with 3-5% CO2 and N2 for 2-4 h (experimental period). In eight studies, the lambs were made hypoxic first, after which we elevated their left atrial pressure by 10-12 Torr for 2-3 h. In 10 additional studies, we reversed the sequence by raising left atrial pressure first followed by addition of hypoxia. In lambs with normal left atrial pressure, alveolar hypoxia increased both pulmonary blood flow and lymph flow, with an associated reduction in lymph-to-plasma protein ratio (L/P). When left atrial pressure was increased in the presence of hypoxia, lymph flow increased by a small amount and L/P decreased further. In lambs with preexisting left atrial pressure elevation, addition of alveolar hypoxia increased both blood flow and lymph flow with no significant change in L/P. These results suggest that in newborn lambs with normal left atrial pressure, alveolar hypoxia increases lung lymph flow mainly by increasing microvascular filtration pressure, whereas in lambs with elevated left atrial pressure, hypoxia increases lymph flow by another mechanism, perhaps by increasing the perfused surface area for fluid filtration.

    View details for Web of Science ID A1988M591900012

    View details for PubMedID 3348427

  • LUNG VASCULAR EFFECTS OF LIPID INFUSION IN AWAKE LAMBS PEDIATRIC RESEARCH Teague, W. G., Raj, J. U., Braun, D., BERNER, M. E., Clyman, R. I., Bland, R. D. 1987; 22 (6): 714-719

    Abstract

    Numerous reports have shown that intravascular lipid infusion may cause pulmonary dysfunction in a variety of species, including humans. To determine the effects of parenteral lipid on neonatal pulmonary hemodynamics, lung fluid filtration, and respiratory gas exchange, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, lymph and plasma protein concentrations, and partial pressures of oxygen and carbon dioxide in arterial blood of 11 awake chronically catheterized lambs that received a 2-3 h control infusion of glucose-saline solution followed by Intralipid at a dose of 67.5, 125, or 250 (mg/h)/kg body weight for 6 h. Intralipid caused an acute dose-dependent increase in pulmonary arterial pressure, with no significant change in cardiac output or left atrial pressure. The pulmonary hypertension, which lasted for at least 2 h, was accompanied by a greater than 50% increase in lung lymph flow and a significant decrease in lymph protein concentration relative to plasma protein concentration. Pulmonary artery pressure gradually decreased to control values during the final 2 h of lipid infusion, but lymph flow remained 35% above control and lymph protein concentration remained low. Lipid infusion also was associated with a modest decrease in PaO2. Both arterial and venous administration of lipid gave similar results. In separate studies, lipid infusion caused a significant increase in plasma concentrations of thromboxane B2, the stable metabolite of thromboxane A2, without affecting plasma concentrations of 6-keto prostaglandin F1 alpha, the stable metabolite of prostacyclin. Pretreatment with imidazole, which attenuated the lipid-induced increase in thromboxane B2 concentration, completely blocked the pulmonary hemodynamic response to lipid.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1987L170000020

    View details for PubMedID 3431956

  • MICROVASCULAR PRESSURES MEASURED BY MICROPUNCTURE IN LUNGS OF NEWBORN RABBITS JOURNAL OF APPLIED PHYSIOLOGY Fike, C. D., LaiFook, S. J., Bland, R. D. 1987; 63 (3): 1070-1075

    Abstract

    The purpose of this study was to determine the pattern of vascular pressure drop in newborn lungs and to define the contribution of active vasomotor tone to this longitudinal pressure profile. We isolated and perfused with blood the lungs from 22 rabbit pups, 5-19 days old. We inflated the lungs to a constant airway pressure of 7 cmH2O, and at constant blood flow, we maintained outflow pressure in the circulation greater than airway pressure at the level of micropuncture (zone 3). By the use of glass micropipettes and a servo-nulling device, we measured pressures in small (20-60 micron diam) subpleural arterioles and venules in the lungs of 13 newborn rabbits. We found that 60% of the pressure drop was in arteries, 31% in microvessels of less than 20-60 micron diam, and 9% in veins. In the lungs of an additional nine rabbit pups we measured microvascular pressures before and after the addition to the perfusate of the vasodilator, papaverine hydrochloride. We found that removal of vasomotor tone resulted in a 33% reduction in total lung vascular resistance, which resulted from a decrease in pressure in arterial vessels, with no change in microvascular pressure. These findings indicate that arteries of greater than 60 micron diam constitute the major source of vascular resistance in isolated perfused newborn rabbit lungs.

    View details for Web of Science ID A1987K088300025

    View details for PubMedID 3115947

  • Pathogenesis of pulmonary edema after premature birth. Advances in pediatrics Bland, R. D. 1987; 34: 175-221

    View details for PubMedID 3318295

  • EFFECT OF HYPOPROTEINEMIA ON LUNG FLUID BALANCE IN AWAKE NEWBORN LAMBS JOURNAL OF APPLIED PHYSIOLOGY Hazinski, T. A., Bland, R. D., Hansen, T. N., SEDIN, E. G., Goldberg, R. B. 1986; 61 (3): 1139-1148

    Abstract

    To study the influence of plasma protein concentration on fluid balance in the newborn lung, we measured pulmonary arterial and left atrial pressures, lung lymph flow, and concentrations of protein in lymph and plasma of eight lambs, 2-3 wk old, before and after we reduced their plasma protein concentration from 5.8 +/- 0.3 to 3.6 +/- 0.6 g/dl. Each lamb underwent two studies, interrupted by a 3-day period in which we drained protein-rich systemic lymph through a thoracic duct fistula and replaced fluid losses with feedings of a protein-free solution of electrolytes and glucose. Each study consisted of a 2-h control period followed by 4 h of increased lung microvascular pressure produced by inflation of a balloon in the left atrium. Body weight and vascular pressures did not differ significantly during the two studies, but lung lymph flow increased from 2.6 +/- 0.1 ml/h during normoproteinemia to 4.1 +/- 0.1 ml/h during hypoproteinemia. During development of hypoproteinemia, the average difference in protein osmotic pressure between plasma and lymph decreased by 1.6 +/- 2 Torr at normal left atrial pressure and by 4.9 +/- 2.2 Torr at elevated left atrial pressure. When applied to the Starling equation governing microvascular fluid balance, these changes in liquid driving pressure were sufficient to account for the observed increases in lung fluid filtration; reduction of plasma protein concentration did not cause a statistically significant change in calculated filtration coefficient. Protein loss did not influence net protein clearance from the lungs nor did it accentuate the increase in lymph flow associated with left atrial pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986E026200049

    View details for PubMedID 3759754

  • LUNG LUMINAL LIQUID CLEARANCE IN NEWBORN LAMBS - EFFECT OF PULMONARY MICROVASCULAR PRESSURE ELEVATION AMERICAN REVIEW OF RESPIRATORY DISEASE Raj, J. U., Bland, R. D. 1986; 134 (2): 305-310

    Abstract

    Postnatal clearance of fetal lung liquid is complete within 6 h of birth in normal lambs. Most of the liquid drains directly from the lung lumen through the interstitium into the bloodstream, as pulmonary lymphatics appear to play a small role in this process (J Appl Physiol 1982; 53:992). To test the possibility that increased pulmonary microvascular pressure might slow the rate of removal of luminal liquid and redirect the liquid into lung lymphatics, we studied 25 lambs, 16 of which had a balloon catheter inflated in the left atrium to maintain lung microvascular pressure 10 torr greater than normal throughout the experiments. We measured pulmonary arterial and left atrial pressures, lung lymph flow, and concentrations of protein in lymph and plasma of 6 anesthetized, mechanically ventilated lambs, 1 to 3 wk old, for 2 to 4 h before and for 6 h after intratracheal instillation of warm, isotonic saline, 6 ml/kg body weight. Extravascular water was measured gravimetrically in lungs of 19 lambs (10 with increased and 9 with normal pulmonary microvascular pressure) killed at 1, 2, and 6 h after saline instillation. The percent liquid cleared from the lungs at 1 and 2 h after saline was significantly less in lambs with increased lung microvascular pressure than it was in lambs with normal microvascular pressure (48 versus 68% at 1 h, 60 versus 77% at 2 h, respectively). Thus, increased lung microvascular pressure slows liquid clearance from the newborn lung. Almost all liquid (greater than 92%) disappeared from the lungs of lambs in both groups by 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986D577000025

    View details for PubMedID 3740657

  • CATION-TRANSPORT IN LUNG EPITHELIAL-CELLS DERIVED FROM FETAL, NEWBORN, AND ADULT-RABBITS JOURNAL OF APPLIED PHYSIOLOGY Bland, R. D., Boyd, C. A. 1986; 61 (2): 507-515

    Abstract

    Recent studies done with fetal and adult sheep and with monolayers of cultured rat alveolar type II cells suggest that active transport of Na+ across the lung epithelium may contribute to liquid absorption from air spaces, an essential component of the normal switch from placental to pulmonary gas exchange at birth. The goals of this work were 1) to study the ontogeny of cation transport in lung epithelial cells derived from fetal, newborn, and adult rabbits and 2) to determine the influence of premature birth, air breathing, labor, and postnatal lung maturation on K+ uptake in these cells. We harvested granular pneumonocytes by tracheal instillation of proteolytic enzymes followed by centrifugation of the dispersed cells over a discontinuous density gradient of metrizamide. This procedure yielded 65-90% granular pneumonocytes, of which more than 80% excluded vital dye. Using freshly isolated cells, we measured uptake of 86Rb+, which mimics transmembrane movement of K+, in the presence or absence of 10(-4) M ouabain and in the presence or absence of 5 X 10(-4) M furosemide or bumetanide. In adult rabbit studies, 86Rb+ uptake was twice as fast in lung epithelial cells (98 +/- 7 nmol X 10(6) cells-1 X h-1) as it was in alveolar macrophages (51 +/- 6 nmol X 10(6) cells-1 X h-1). Ouabain inhibited 55-60% of the uptake by pneumonocytes, and "loop" diuretics inhibited an additional 15-20%. The rate of 86Rb+ uptake in fetal cells was less than 10% (6 +/- 1 nmol X 10(6) cells-1 X h-1) of the rate in adult cells; ouabain inhibited 80-85% of 86Rb+ uptake in fetal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986D621100018

    View details for PubMedID 3745043

  • MICROVASCULAR PRESSURES MEASURED BY MICROPIPETTES IN ISOLATED EDEMATOUS RABBIT LUNGS JOURNAL OF APPLIED PHYSIOLOGY Raj, J. U., Bland, R. D., LaiFook, S. J. 1986; 60 (2): 539-545

    Abstract

    To study the mechanical effects of lung edema on the pulmonary circulation, we determined the longitudinal distribution of vascular resistance in the arteries, veins, and microvessels, and the distribution of blood flow in isolated blood-perfused rabbit lungs with varying degrees of edema. Active vasomotor changes were eliminated by adding papaverine to the perfusate. In three groups of lungs with either minimal [group I, mean wet-to-dry weight ratio (W/D) = 5.3 +/- 0.6 (SD), n = 7], moderate (group II, W/D = 8.5 +/- 1.2, n = 10), or severe (group III, W/D = 9.9 +/- 1.6, n = 5) edema, we measured by direct micropuncture the pressure in subpleural arterioles and venules (20-60 micron diam) and in the interstitium surrounding these vessels. We also measured pulmonary arterial and left atrial pressures and lung blood flow, and in four additional experiments we used radio-labeled microspheres to determine the distribution of blood flow during mild and severe pulmonary edema. In lungs with little or no edema (group I) we found that 33% of total vascular pressure drop was in arteries, 60% was in microvessels, and 7% was in veins. Moderate edema (group II) had no effect on total vascular resistance or on the vascular pressure profile, but severe edema (group III) did increase vascular resistance without changing the longitudinal distribution of vascular resistance in the subpleural microcirculation. Perivascular interstitial pressure relative to pleural pressure increased from 1 cmH2O in group I to 2 in group II to 4 in group III lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986A125700026

    View details for PubMedID 3949659

  • OXYGEN-INDUCED LUNG MICROVASCULAR INJURY IN NEUTROPENIC RABBITS AND LAMBS JOURNAL OF APPLIED PHYSIOLOGY Raj, J. U., Hazinski, T. A., Bland, R. D. 1985; 58 (3): 921-927

    Abstract

    We did two studies to see if severe neutropenia might reduce the severity or delay development of O2-induced lung microvascular injury. First, we treated 11 rabbits with nitrogen mustard until their circulating neurophil count decreased to less than 50/microliters of blood, after which the rabbits breathed pure O2 until death; nine other rabbits received no nitrogen mustard and had normal numbers of circulating neutrophils during O2 breathing. All rabbits died of respiratory failure with pulmonary edema, and although chemotherapy decreased the number of neutrophils in the lungs by greater than 90%, it did not influence survival time or extravascular lung water content. To see if severe neutropenia might slow the development of O2-induced lung microvascular injury, we assessed the effects of sustained hyperoxia on lung fluid balance in unanesthetized lambs treated with hydroxyurea, so that their absolute neutrophil count was less than 50/microliters of blood. We measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma during a 2- to 4-h control period and then daily for 2 to 4 h as the lambs continuously breathed pure O2. After 3 days of hyperoxia, lymph flow doubled and the concentration of protein in lymph increased from 3.3 +/- 0.5 to 4.2 +/- 0.3 g/dl. Tracer studies with 125I-albumin before and 3 days after the start of O2 breathing confirmed the development of increased lung vascular permeability to protein. All lambs died of respiratory failure with pulmonary edema after 3-5 days in O2.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1985ADR9000035

    View details for PubMedID 3980393

  • LUNG FLUID BALANCE IN HYPOXIC LAMBS PEDIATRIC RESEARCH Hansen, T. N., Haberkern, C. M., Hazinski, T. A., Bland, R. D. 1984; 18 (5): 434-440

    Abstract

    In spontaneously breathing newborn lambs, alveolar hypoxia increases lung microvascular pressure, which causes lung lymph flow to increase and the concentration of protein in lymph to decrease. To see if this response derives from hypoxia itself rather than from the change in breathing pattern that occurs during hypoxia, we measured lung vascular pressures, pleural pressure, cardiac output, and lung lymph flow in 12 anesthetized lambs that were ventilated at a fixed rate and tidal volume, first with air, then with 10-14% O2 in nitrogen. Alveolar hypoxia did not affect pleural pressure, but pulmonary arterial pressure increased from 19 to 32 torr, lung lymph flow increased from 2.20 to 3.83 ml/h and lymph protein concentration decreased from 3.4 to 2.8 g/dl. To be certain that the increased lymph flow associated with hypoxia is not simply the result of an acute release of fluid from the lungs and to assess the effects of carbon dioxide on lymph flow during hypoxia, we next studied six unanesthetized lambs kept hypoxic for a total of 12 h. After a 2-4-h period in air the lambs breathed 9-11% O2 in nitrogen for 2-4 h, then 8-11% O2 and 3-5% CO2 in nitrogen for 8-10 h. In these lambs we injected intravenously radioactive albumin and measured its uptake in lymph to see if sustained hypoxia alters microvascular permeability to protein in the lungs. In these experiments pulmonary arterial pressure increased from 17 to 37 torr, lung lymph flow increased from 1.74 to 3.28 ml/h, and lymph protein concentration decreased from 3.8 to 3.1 g/dl during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1984SP48800009

    View details for PubMedID 6728570

  • EFFECTS OF ASPHYXIA ON LUNG FLUID BALANCE IN BABY LAMBS JOURNAL OF CLINICAL INVESTIGATION Hansen, T. N., Hazinski, T. A., Bland, R. D. 1984; 74 (2): 370-376

    Abstract

    The purpose of this study was to assess the effects of combined hypoxia and hypercapnia and of severe asphyxia on lung water balance and protein transport in newborn lambs. We studied ten 2-4-wk-old anesthetized lambs which were mechanically ventilated first with air for 2-3 h, then with 10-12% oxygen in nitrogen for 2-4 h, and then with 10-12% oxygen and 10-12% carbon dioxide in nitrogen for 2-4 h. Next we stopped their breathing for 1-2 min to produce severe asphyxia, after which we followed their recovery in air for 2-4 h. In 5 of the 10 lambs we intravenously injected radioactive albumin and measured its turnover time between plasma and lymph during the baseline period and after recovery from asphyxia. During alveolar hypoxia alone, mean pulmonary arterial pressure increased 60% and lung lymph flow increased 74%, whereas lymph protein concentration decreased from 3.47 +/- 0.13 to 2.83 +/- 0.15 g/dl. Cardiac output, left atrial pressure, and plasma protein concentration did not change. When carbon dioxide was added to the inspired gas mixture, pulmonary arterial pressure increased 22%, cardiac output increased 13%, lung lymph flow increased 33%, and lymph protein concentration decreased from 2.83 +/- 0.15 to 2.41 +/- 0.13 g/dl. Left atrial pressure and plasma protein concentration did not change. After 60-90 s of induced asphyxia, vascular pressures and lung lymph flow rapidly returned to values the same as those obtained during the baseline period. The turnover time for radioactive albumin between plasma and lymph was the same between the baseline and recovery periods (185 +/- 16 vs. 179 +/- 12 min). The ratio of albumin to globulin in lymph relative to the same ratio in plasma did not change during any phase of these experiments. Five lambs killed after recovery from asphyxia had significantly less blood and extravascular water in their lungs than control lambs had. We conclude that in the newborn lamb both alveolar hypoxia and alveolar hypoxia with hypercapnia increase lung lymph flow by increasing filtration pressure in the microcirculation, but neither hypoxia with hypercapnia nor brief severe asphyxia alters the protein permeability of the pulmonary microcirculation.

    View details for Web of Science ID A1984TC73300008

    View details for PubMedID 6430959

  • Neutrophil depletion does not prevent oxygen-induced lung injury in rabbits. Chest Raj, J. U., Bland, R. D. 1983; 83 (5): 20S-21S

    View details for PubMedID 6839842

  • VIBRATORY VENTILATION DECREASES FILTRATION OF FLUID IN THE LUNGS OF NEWBORN LAMBS CIRCULATION RESEARCH Raj, J. U., Goldberg, R. B., Bland, R. D. 1983; 53 (4): 456-463

    Abstract

    To compare effects of vibratory and mechanical ventilation on fluid balance in the newborn lung, we measured pulmonary arterial and left atrial pressures, pleural and airway pressures, lung blood flow and lymph flow, and concentrations of protein in lymph and plasma of 19 healthy lambs, 2-4 weeks old, during a 2- to 4-hour period of spontaneous breathing, followed by 4-8 hours of mechanical ventilation at 30 breaths/min and 4-8 hours of vibratory ventilation, in which the lambs received 1650 whiffs of air/min. In 8 of 22 studies, we increased lung microvascular pressure by filling a balloon catheter in the left atrium with saline. There was no significant difference in mean airway pressure during the two types of ventilation. Despite higher lung vascular pressures, lymph flow was less and lymph protein concentration was greater during vibratory than during mechanical ventilation. These findings are consistent with reduced lung fluid filtration, possibly from reduced pulmonary blood flow and increased perimicrovascular pressure, during vibratory ventilation. In eight lambs killed after 8 hours of vibratory ventilation, extravascular lung water was normal and microscopy showed no edema. We conclude that vibratory ventilation has no adverse effect on lung fluid balance and may benefit lambs by decreasing net filtration of fluid into their lungs.

    View details for Web of Science ID A1983RP43700003

    View details for PubMedID 6627605

  • HIGH-FREQUENCY MECHANICAL VENTILATION IN THE TREATMENT OF NEONATAL RESPIRATORY-DISTRESS INTERNATIONAL ANESTHESIOLOGY CLINICS Bland, R. D., SEDIN, E. G. 1983; 21 (3): 125-147

    View details for Web of Science ID A1983RD20100009

    View details for PubMedID 6413419

  • DYNAMICS OF PULMONARY WATER BEFORE AND AFTER BIRTH ACTA PAEDIATRICA SCANDINAVICA Bland, R. D. 1983: 12-20

    Abstract

    In fetal life an electrochemical gradient across the pulmonary epithelium causes liquid to flow from the microcirculation of the lungs through the interstitium into potential air spaces. That liquid is rich in chloride (greater than 150 meq/l) and almost free of protein (less than 0.03 g/dl). At birth rapid reversal of the direction of liquid flow is essential for a smooth transition from placental to pulmonary gas exchange. Removal of liquid from the lungs begins even before birth. In fetal rabbits and lambs, a substantial decrease in extravascular lung water occurs late in gestation and during labor. When breathing begins, transpulmonary pressure inflates the lungs and displaces residual liquid from terminal respiratory units into the interstitium. Fluid accumulates in connective tissue spaces surrounding large pulmonary blood vessels, distant from sites of gas exchange. The concentration of protein in the interstitium decreases, thereby increasing the transvascular gradient of protein osmotic pressure. Air entry into the lungs also decreases hydraulic pressure in the pulmonary microcirculation and increases pulmonary blood flow, which expands microvascular surface area for fluid exchange in the lungs. These developments facilitate reabsorption of water into the pulmonary vascular bed. In lambs, the postnatal increase in lung lymph flow is small and transient, accounting for only 10-15% of the total amount of liquid drained from the lungs after birth. Normally, the pulmonary microcirculation directly absorbs most of the fetal lung liquid that is present at birth.

    View details for Web of Science ID A1983QZ98900003

    View details for PubMedID 6351531

  • EDEMA FORMATION IN THE LUNGS AND ITS RELATIONSHIP TO NEONATAL RESPIRATORY-DISTRESS ACTA PAEDIATRICA SCANDINAVICA Bland, R. D. 1983: 92-99

    Abstract

    Pulmonary edema is an important feature of many newborn lung diseases, including respiratory distress from severe perinatal asphyxia, heart failure, hyaline membrane disease, pneumonitis from group B beta-hemolytic streptococcus, and chronic lung disease (bronchopulmonary dysplasia). Neonatal pulmonary edema often results from increased filtration pressure in the microcirculation of the lungs. This occurs during sustained hypoxia, in left ventricular failure associated with congenital heart disease or myocardial dysfunction, following excessive intravascular infusions of blood, colloid, fat, or electrolyte solution, and in conditions that increase pulmonary blood flow. Low intravascular protein osmotic pressure from hypoproteinemia may predispose infants to pulmonary edema. Hypoproteinemia is common in infants who are born prematurely. Large intravascular infusions of protein-free fluid further decrease the concentration of protein in plasma and thereby facilitate edema formation. Lymphatic obstruction by air (pulmonary interstitial emphysema) or fibrosis (long-standing lung disease) also may contribute to the development of edema. Bacteremia, endotoxemia, and prolonged oxygen breathing injure the pulmonary microvascular endothelium and cause protein-rich fluid to accumulate in the lungs. The risk of neonatal pulmonary edema can be reduced by several therapeutic measures designed to lessen filtration pressure, increase plasma protein osmotic pressure, and prevent or reduce the severity of lung injury.

    View details for Web of Science ID A1983QZ98900018

    View details for PubMedID 6577779

  • STUDIES OF LUNG FLUID BALANCE IN NEWBORN LAMBS ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Bland, R. D., Hansen, T. A., Hazinski, T. A., Haberkern, C. M., Bressack, M. A. 1982; 384 (MAY): 126-145

    View details for Web of Science ID A1982PK60500013

    View details for PubMedID 6953816

  • VITAMIN-E DOES NOT PREVENT OXYGEN-INDUCED LUNG INJURY IN NEWBORN LAMBS PEDIATRIC RESEARCH Hansen, T. N., Hazinski, T. A., Bland, R. D. 1982; 16 (7): 583-587

    View details for Web of Science ID A1982NV77200019

    View details for PubMedID 7110779

  • EDEMA FORMATION IN THE NEWBORN LUNG CLINICS IN PERINATOLOGY Bland, R. D. 1982; 9 (3): 593-611

    Abstract

    Pulmonary edema is an important cause of respiratory distress in newborn infants. It occurs with severe perinatal asphyxia, heart failure, hyaline membrane disease, persistent patency of the ductus arteriosus, pneumonitis from group B beta-hemolytic streptococcus, and chronic lung disease (bronchopulmonary dysplasia). Neonatal pulmonary edema often develops from increased pressure in the microcirculation of the lungs. This may occur in conjunction with sustained hypoxia; left ventricular failure associated with congenital heart disease or myocardial dysfunction; following excessive intravascular infusions of blood, colloid, fat, or electrolyte solution and in conditions that increase pulmonary blood flow. Low intravascular protein osmotic pressure from hypoproteinemia may predispose infants to pulmonary edema. Hypoproteinemia is common in infants who are born prematurely. Large intravascular infusions of protein-free fluid further decrease the concentration of protein in plasma and thereby facilitate edema formation. Lymphatic obstruction by air (pulmonary interstitial emphysema of fibrosis (chronic lung disease) also may contribute to the development of edema. Bacteremia, endotoxemia, and prolonged oxygen-breathing injure the pulmonary microvascular endothelium and cause protein-rich fluid to accumulate in the lungs. Epithelial protein leaks may develop when the transpulmonary pressure needed to inflate the lungs increases because of high surface tension at the air-liquid interface. Fibrin clots from in some of the air spaces, which in combination with atelectasis and edema constitute the pathologic features of hyaline membrane disease. The risk of neonatal pulmonary edema can be reduced by several therapeutic measures designed to lessen fluid filtration pressure, increase plasma protein osmotic pressure, and prevent or reduce the severity of lung injury.

    View details for Web of Science ID A1982PW64900008

    View details for PubMedID 6761039

  • ONTOGENY AND REGULATION OF CORTICOSTEROID BINDING GLOBULIN CAPACITY IN PLASMA OF FETAL AND NEWBORN LAMBS ENDOCRINOLOGY Ballard, P. L., KITTERMAN, J. A., Bland, R. D., Clyman, R. I., Gluckman, P. D., Platzker, A. C., Kaplan, S. L., Grumbach, M. M. 1982; 110 (2): 359-366

    Abstract

    The developmental pattern for plasma corticosteroid binding globulin (CBG) and unbound corticoids was studied in fetal and newborn sheep. CBG capacity in the fetus increased progressively from a value of 1.6 micrograms cortisol bound/dl plasma at 75 days gestation to 7.1 micrograms/dl at 141 days (n = 249), with a greater rate of increase after 120 days. By contrast total plasma proteins increased by about 50% during the third trimester. There was an accelerated increase in the concentration of both CBG and total proteins with labor, apparently reflecting hemoconcentration. The rate of increase in total plasma corticoids was similar to that for CBG capacity; however, corticoids began their major rise later in gestation (approximately 130 days). The concentration of unbound corticoids was 0.09 micrograms/dl at 115 days and did not increase until after 135 days, reaching a maximal level of 1.87 micrograms/dl on the day before spontaneous term delivery. After birth, CBG capacity decreased from a prepartum value of 11.4 micrograms/dl to 0.6 micrograms/dl at 14 days of age, whereas total plasma proteins were constant. Total and free corticoid levels also decreased postnatally, but at a slower rate than for CBG. The expected rise in fetal CBG capacity during the third trimester did not occur in hydranencephalic, stalk-sectioned, and hypophysectomized fetuses with loss of pituitary function. Under the conditions used, there was no precocious increase in CBG concentrations with infusion of hydrocortisone, PRL, or 17 beta-estradiol to intact fetuses, and infusion of ACTH to a hypophysectomized fetus did not affect the level of CBG. Thus, there is a marked increase in CBG capacity prenatally and a rapid decrease after birth. These changes in CBG may be responsible, at least in part, for the similar changes in total corticoid concentrations. We conclude that pituitary hormone(s) regulate CBG in the sheep fetus and speculate that this effect involves the placenta.

    View details for Web of Science ID A1982NA22100008

    View details for PubMedID 7056203

  • LUNG FLUID BALANCE IN LAMBS BEFORE AND AFTER BIRTH JOURNAL OF APPLIED PHYSIOLOGY Bland, R. D., Hansen, T. N., Haberkern, C. M., Bressack, M. A., Hazinski, T. A., Raj, J. U., Goldberg, R. B. 1982; 53 (4): 992-1004

    Abstract

    To study lung fluid balance before and after birth, we measured lung lymph flow and concentrations of protein in lymph and plasma of 22 unanesthetized fetal lambs and compared results with previous studies done on 26 newborn lambs, 1-2 wk old. Lymph flow, relative to lung mass, was less in fetuses than in newborns; lymph protein clearance was not significantly different. Less lymph flow before birth probably reflects less available surface area for fluid exchange in microcirculation of fetal lungs, compared with newborn lungs, with no difference in endothelial permeability to protein. Extravascular lung water, measured gravimetrically for 24 fetuses (10 without labor, nine in labor, five 6 h after vaginal birth), decreased by 45% (15 +/- 2 g/kg body wt) before birth and by an additional 38% (6 +/- 1 g/kg) after birth. In five lambs killed after birth, we measured lung lymph flow before and during labor and for 6 h after breathing began. Lymph flow was unaffected by labor but increased transiently after birth, accounting for 11% of the liquid removed from lungs postnatally. Liquid clearance studies performed in eight anesthetized 3-wk-old lambs confirmed the observation that lung lymphatics drain only a small fraction of liquid in potential air spaces. Most of that liquid probably leaves the lungs directly through pulmonary circulation.

    View details for Web of Science ID A1982PL49100029

    View details for PubMedID 7153132

  • EFFECT OF HYPERCAPNIA ON NET FILTRATION OF FLUID IN THE LUNGS OF AWAKE NEWBORN LAMBS JOURNAL OF APPLIED PHYSIOLOGY Haberkern, C. M., Bland, R. D. 1981; 51 (2): 423-427

    Abstract

    To study the effect of hypercapnia on net transvascular filtration of fluid in newborn lungs, we measured pulmonary arterial and left pressures and collected lung lymph from 11 awake 2-wk-old lambs as they spontaneously breathed a gas mixture rich in carbon dioxide. After a 2-h control period in air, the lambs breathed 8-11% carbon dioxide mixed with air and nitrogen for 2-6 h. Average pulmonary arterial pressure and blood flow to the lungs increased during hypercapnia, but pulmonary vascular resistance did not change. In all cases, hypercapnia led to an acute transient increase in lymph flow. During sustained hypercapnia, however, flow of lymph was not significantly different from flow measured during the control period. The concentration of protein in lymph decreased at the onset of hypercapnia and remained low during sustained hypercapnia. These results suggest that acute hypercapnia increases net filtration by increasing the transvascular gradient of hydraulic pressure, whereas, in a "steady-state," neither hypercapnia nor the tachypnea that accompanies it alters net transvascular filtration of fluid in the lungs of unanesthetized newborn animals.

    View details for Web of Science ID A1981MC10900027

    View details for PubMedID 7263449

  • INTRAVENOUS-INFUSION OF TOLAZOLINE REDUCES PULMONARY VASCULAR-RESISTANCE AND NET FLUID FILTRATION IN THE LUNGS OF AWAKE, HYPOXIC NEWBORN LAMBS AMERICAN REVIEW OF RESPIRATORY DISEASE Bressack, M. A., Bland, R. D. 1981; 123 (2): 217-221

    View details for Web of Science ID A1981LD33100016

    View details for PubMedID 7235360

  • CLEARANCE OF LIQUID FROM LUNGS OF NEWBORN RABBITS JOURNAL OF APPLIED PHYSIOLOGY Bland, R. D., McMillan, D. D., Bressack, M. A., Dong, L. 1980; 49 (2): 171-177

    Abstract

    Apparent inconsistencies in the results of previous studies led us to reexamine the process by which fluid leaves the lungs of newborn rabbits after birth. We measured pulmonary blood volume, extravascular lung water, and the size of perivascular cuffs of fluid in frozen sections of lung obtained from 166 full-term rabbits (31 days gestation) born vaginally or by cesarean section. We killed the rabbits by giving them barbiturate intraperitoneally and immersing them in liquid nitrogen before they breathed or at randomly predetermined intervals from 5 min to 24 h after birth. We found that a) pulmonary blood volume of both groups of rabbits increased soon after birth, b) extravascular lung water per gram of dry lung tissue was greater at birth in rabbits born by cesarean section than in those born vaginally, c) extravascular lung water did not begin to decrease in either group of animals until 30-60 min postnatally, after which it decreased progressively for 24 h, and d) the rate of fluid clearance and pattern of puddling around pulmonary vessels was similar in both groups of rabbits, with maximal perivascular cuffs 30 min after birth, followed by diminution of cuff size as the lungs shed water.

    View details for Web of Science ID A1980KE70900001

    View details for PubMedID 7399999

  • SPECIAL CONSIDERATIONS IN OXYGEN-THERAPY FOR INFANTS AND CHILDREN AMERICAN REVIEW OF RESPIRATORY DISEASE Bland, R. D. 1980; 122 (5): 45-54

    Abstract

    There are several unique aspects of O2 therapy in infants. Inhalation of O2 by preterm infants decreases the frequency of apnea and cyanosis, and increases the ventilatory response to CO2, but the reasons for this are unclear. Immature infants receiving O2 therapy are subject to retinopathy, but we do not know the magnitude or duration of hyperoxia necessary to damage the developing retina. Newborns with persistent pulmonary hypertension, without radiographic signs of pulmonary disease, frequently remain hypoxemic despite breathing 100% O2. In these infants, the unresponsiveness of teh postnatal pulmonary circulation to high concentrations of inspired O2 needs elucidation. Babies with respiratory failure who are treated with O2 and mechanical ventilation often acquire chronic pulmonary disease. The etiologic importance of O2 compared to postive airway pressure in the development of this condition remains controversial. Some laboratory studies suggest that newborn animals are resistant to pulmonary injury from O2; other studies indicate that youth offers no protection. The results of experiments carried out with newborn mice and lambs provide evidence that diet may be an important element in the susceptibility of newborn animals to pulmonary O2 toxicity.

    View details for Web of Science ID A1980KY17800010

    View details for PubMedID 6779680

  • ALVEOLAR HYPOXIA INCREASES LUNG FLUID FILTRATION IN UNANESTHETIZED NEWBORN LAMBS CIRCULATION RESEARCH Bressack, M. A., Bland, R. D. 1980; 46 (1): 111-116

    View details for Web of Science ID A1980JA35900013

    View details for PubMedID 7349911

  • HIGH-FREQUENCY MECHANICAL VENTILATION IN SEVERE HYALINE-MEMBRANE DISEASE - AN ALTERNATIVE TREATMENT CRITICAL CARE MEDICINE Bland, R. D., Kim, M. H., Light, M. J., WOODSON, J. L. 1980; 8 (5): 275-280

    Abstract

    Twenty-four preterm infants with respiratory failure from severe hyaline membrane disease (HMD) received mechanical ventilation at high respiratory frequencies. The average birthweight of the infants was 1244 +/- 301 g, and 7 babies weighed less than 1000 g. The average gestational age was 30 +/- 2 weeks, and 6 infants were born at 28 weeks or less. The method of ventilation included (1) respiratory frequencies of 60--110/min, sometimes with brief manual ventilation at more rapid rates, (2) peak inflation pressures (PIP) of less than 35 cm H2O, (3) inspiratory durations of 0.15--0.25 sec, (4) positive end-expiratory pressure (PEEP) of 4--9 cm H2O, and (5) weaning from mechanical ventilation by reducing tidal volume until peak inflation pressure (PIP) reached 20--25 cm H2O, whereupon respiratory frequency was decreased. PaCO2 was kept at 30--40 torr and PaO2 at 60--80 torr. Of the infants, 22 survived (92%) with few major complications.

    View details for Web of Science ID A1980JQ40800001

    View details for PubMedID 6989552

  • LUNG FLUID BALANCE IN HYPOXIC, AWAKE NEWBORN LAMBS AND MATURE SHEEP BIOLOGY OF THE NEONATE Bland, R. D., Bressack, M. A., Haberkern, C. M., Hansen, T. N. 1980; 38 (5-6): 221-228

    Abstract

    To study the pulmonary vascular response to hypoxia and associated transvascular flow of fluid into the lungs of newborn lambs and mature sheep, we collected lung lymph and measured pulmonary vascular pressures and blood flow in 14 unanesthetized lambs and 9 sheep breathing 10-12% oxygen for 3-6 h after a 2-hour control period in air. In both groups of animals, pulmonary arterial pressure, blood flow, and lung vascular resistance increased with hypoxia, but only in lambs did the flow of lymph increase and th concentration of protein in lymph decrease with hypoxia. These results suggest that hypoxia increased transvascular filtration of fluid into the lungs of the lambs by increasing hydraulic pressure in the pulmonary microcirculation. In sheep, the vascular response to hypoxia did not increase lung fluid filtration. Hypoxia had no effect on microvascular permeability to protein in the lungs of either group of animals.

    View details for Web of Science ID A1980KL11300001

    View details for PubMedID 7417604

  • PULMONARY OXYGEN-TOXICITY - INCREASED MICRO-VASCULAR PERMEABILITY TO PROTEIN IN UNANESTHETIZED LAMBS LYMPHOLOGY Bressack, M. A., McMillan, D. D., Bland, R. D. 1979; 12 (3): 133-139

    Abstract

    To study transvascular filtration of fluid and microvascular permeability to protein in the lung during prolonged hyperoxia, we measured lung lymph flow, protein transport, and simultaneous pulmonary vascular pressures of six lambs breathing 100 percent O2 for five days. Lymph flow doubled, protein flow increased by 131 percent, and radioactive tracer studies demonstrated a clearcut increase in pulmonary microvascular permeability to protein after five days of continuous O2 breathing.

    View details for Web of Science ID A1979HM76300004

    View details for PubMedID 542018

  • LABOR DECREASES THE LUNG WATER-CONTENT OF NEWBORN RABBITS AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Bland, R. D., Bressack, M. A., McMillan, D. D. 1979; 135 (3): 364-367

    Abstract

    To test the prevailing concept that drainage of fetal lung liquid begins after birth, we measured extravascular lung water content of 47 fetal rabbits born at term gestation, with or without prior labor. Rabbits born after labor, either vaginally or operatively, had less water in their lungs than those delivered by cesarean section without preceding labor; there was no difference in lung water content between rabbits born vaginally or operatively after labor. These results suggest that reduction in the volume of fetal lung liquid in rabbits normally begins before birth and depends on the experience of labor, not the mode of delivery.

    View details for Web of Science ID A1979HN76500016

    View details for PubMedID 484627

  • LUNG FLUID BALANCE IN AWAKE NEWBORN LAMBS WITH PULMONARY-EDEMA FROM RAPID INTRAVENOUS-INFUSION OF ISOTONIC SALINE PEDIATRIC RESEARCH Bland, R. D., Bressack, M. A. 1979; 13 (9): 1037-1042

    Abstract

    To study pulmonary transvascular filtration of fluid and the normal adaptive response of newborn animals to excessive water in the lungs, we measured lung lymph flow, pulmonary vascular pressures, and the concentration of protein in lymph and plasma of nine unanesthetized 1- to 3-wk-old lambs, before, during, and after a rapid iv infusion of isotonic saline, 130-250 ml/kg.hr for 3-4 hr. During infusions, lung vascular pressures increased, the transvascular gradient of protein osmotic pressure decreased, and there was a 2- to 5-fold increase of lung lymph flow. When infusions stopped, lymph flow decreased, as the concentration of protein in plasma increased and pulmonary vascular pressures decreased to new steady-state levels. The concentration of protein in lymph did not change for several hours after the infusions. Body weight increased by 28% and extravascular lung water content was 19% above normal after saline; these changes were associated with mild tachypnea, hypercarbia, and hypoxemia. Sections of lung from these lambs had prominent cuffs of fluid surrounding large blood vessels.

    View details for Web of Science ID A1979HJ20400018

    View details for PubMedID 503655

  • DECREASED PULMONARY TRANSVASCULAR FLUID FILTRATION IN AWAKE NEWBORN LAMBS AFTER INTRAVENOUS FUROSEMIDE JOURNAL OF CLINICAL INVESTIGATION Bland, R. D., McMillan, D. D., Bressack, M. A. 1978; 62 (3): 601-609

    Abstract

    We studied the effect of furosemide on pulmonary transvascular filtration of fluid and microvascular permeability to plasma proteins by measuring steady-state lung lymph flow and protein flow, pulmonary arterial and left atrial pressures in nine 1-wk-old unanesthetized lambs before and after rapid intravenous infusion of furosemide, 1 mg/kg in 10 experiments and 8 mg/kg in 5 experiments. With rapid diuresis induced by furosemide (an eightfold increase in urine flow), lung vascular pressures decreased, protein concentrations of lymph and plasma increased, and there was a consistent decrease in lymph flow and lymph protein flow, more pronounced after the larger dose. Five additional lambs received 8 mg/kg of furosemide intravenously in the presence of saline-induced pulmonary edema; in these experiments, the decrease in vascular pressures, increase in transvascular protein gradient, and decrease in lymph flow were greater than in lambs without pulmonary edema. These findings suggest that furosemide decreases transvascular filtration of fluid in the lung by diminishing the transvascular hydraulic pressure gradient and increasing the transvascular gradient for protein osmotic pressure. In five acute experiments on anesthetized lambs with kidneys removed, 8 mg/kg of intravenous furosemide decreased lymph flow one-half as much as it did in the presence of kidneys, with no change in lung vascular pressures or protein concentrations. The results of experiments in lambs without kidneys are consistent with a reduction in the vascular surface area for exchange of fluid and protein in the lung.

    View details for Web of Science ID A1978FM77200014

    View details for PubMedID 690187

  • PULMONARY TRANSVASCULAR FLUID FILTRATION AND MICROVASCULAR PERMEABILITY TO PLASMA-PROTEINS IN AWAKE NEWBORN LAMBS CHEST Bland, R. D., McMillan, D. D. 1977; 71 (2): 274-274

    View details for Web of Science ID A1977CU72900015

    View details for PubMedID 836370

  • EFFECTS OF ALVEOLAR HYPOXIA ON LUNG FLUID AND PROTEIN TRANSPORT IN UNANESTHETIZED SHEEP CIRCULATION RESEARCH Bland, R. D., Demling, R. H., Selinger, S. L., Staub, N. C. 1977; 40 (3): 269-274

    Abstract

    To determine whether hypoxia directly affects pulmonary microvascular filtration of fluid or permeability to plasma proteins, we measured steady state lung lymph flow and protein transport in eight unanesthetized sheep breathing 10% O2 in N2 for 4 hours. We also studied three sheep breathing the same gas mixture for 48 hours. We surgically prepared the sheep to isolate and collect lung lymph and to measure average pulmonary arterial (Ppa) and left atrial (Pla) pressures. We placed a balloon catheter in the left atrium to elevate Pla. After recovery, the sheep breathed air through a tracheostomy for 2-4 hours, followed by 4 or 48 hours of hypoxia. In 13 4-hour studies, the average arterial PO2 fell from 97 to 38 torr; Ppa rose from 20 to 33 cm H2O; and lung lymph flow and lymph protein flow were unchanged. We also found that during 48-hour hypoxia, with a sustained elevation in Ppa and a decline in Pla, lymph flow and protein flow did not increase. In four sheep, we also raised Pla for 4 hours, followed by 4 hours of hypoxia with elevated Pla. Again, despite the added stress of elevated Pla, we found that lymph flow and lymph protein flow remained constant during hypoxia. We conclude that severe alveolar hypoxia, for 4 or 48 hours, alone or with increased pulmonary microvascular pressure, produced no change in lung fluid filtration or protein permeability, a finding supported by normal postmortem histology and extravascular lung water content.

    View details for Web of Science ID A1977CY44600008

    View details for PubMedID 13942

  • LUNG FLUID-DYNAMICS IN AWAKE NEWBORN LAMBS JOURNAL OF CLINICAL INVESTIGATION Bland, R. D., McMillan, D. D. 1977; 60 (5): 1107-1115

    Abstract

    We measured steady-state lung lymph flow, lymph protein flow, and simultaneous pulmonary vascular pressures in 12 1-wk-old unanesthetized lambs and compared these measurements to those of previous studies, performed under similar conditions, on nine awake adult sheep. The purpose of these experiments was to compare newborn and adult sheep with respect to transvascular filtration of fluid and microvascular permeability to plasma proteins. We prepared the lambs surgically to isolate and collect lung lymph and measure average pulmonary arterial and left atrial pressures, allowing at least 2 days for the lambs to recover from surgery before studies began. Lambs had higher pulmonary arterial and left atrial pressures, lower lymph and plasma protein concentrations, and 57% more lymph flow per gram of dry bloodless lung than sheep; the difference in protein flow between lambs and sheep was not significant. Protein concentration in lymph relative to that in plasma was significantly lower in lambs than in sheep; but the ratio of albumin concentration to globulin concentration in both lymph and plasma was almost identical in the two groups of animals. Extravascular lung water per gram of dry bloodless lung was greater in lambs (4.82+/-0.11 g) than in sheep (4.45+/-0.08 g), but there was no histologic evidence of pulmonary edema in either group of animals. These findings suggest that lambs have more transvascular filtration of fluid per unit lung mass than sheep, but that microvascular sites for protein exchange do not differ appreciably in lambs and sheep. To test this conclusion, we measured steady-state lymph flow in three lambs before and after raising pulmonary microvascular pressure by rapid intravenous infusion of saline. Lymph flow increased as a function of the net transvascular driving pressure (hydraulic pressure gradient-protein osmotic pressure gradient). This response was almost identical to that of four sheep with pulmonary microvascular pressure augmented by inflation of a balloon in the left atrium. In eight lambs we measured the time for intravenously injected (125)I-albumin to equilibrate in lymph at half the specific activity of plasma: the protein tag equilibrated faster than in sheep. This difference could be explained partly by the higher pulmonary arterial and left atrial pressures of lambs than sheep, and possibly by the presence of more microvascular sites for protein exchange relative to the volume of distribution of protein in the lung of the younger animals.

    View details for Web of Science ID A1977EA08500017

    View details for PubMedID 908754

  • MOVEMENT OF WATER AND PROTEIN IN FETAL AND NEWBORN LUNG ANNALES DE RECHERCHES VETERINAIRES Bland, R. D., McMillan, D. D., Bressack, M. A. 1977; 8 (4): 418-427

    View details for Web of Science ID A1977ER69600011

    View details for PubMedID 615514

  • RAPID INFUSION OF SODIUM-BICARBONATE AND ALBUMIN INTO HIGH-RISK PREMATURE-INFANTS SOON AFTER BIRTH - CONTROLLED, PROSPECTIVE TRIAL AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Bland, R. D., Clarke, T. L., HARDEN, L. B. 1976; 124 (3): 263-267

    Abstract

    We conducted a controlled, prospective trial to evaluate the effectiveness of rapidly infusing sodium bicarbonate (NaHCO3) and salt-poor albumin into high-risk, premature infants in the first 2 hours of life. Fifty-three infants, randomized into one of four treatment groups, received 8 ml. per kilogram of a solution containing either (A) glucose in water, (B) salt-poor albumin, (C) NaHCO3, or (D) a combination of albumin and NaHCO3. After the initial infusion, the babies received no colloid or alkali solutions until 4 hours of age. We managed them supportively with warmth, appropriate oxygen administration, isotonic fluid infusion, and close monitoring. Among the infants who received alkali, 14 of 26 acquired the respiratory distress syndrome (RDS), 11 died, and four had intracranial hemorrhage. Among babies who received no alkali, RDS occurred in 11 of 27, 5 died, and none had intracranial hemorrhage. These results do not support the common practice of rapidly infusing NaHCO3 into high-risk, premature infants, and they suggest that the early management of such infants needs renewed critical evaluation.

    View details for Web of Science ID A1976BF20000009

    View details for PubMedID 2013

  • EFFECT OF ACUTE HEMORRHAGIC-SHOCK ON PULMONARY MICROVASCULAR FLUID FILTRATION AND PROTEIN PERMEABILITY IN SHEEP SURGERY Demling, R. H., Selinger, S. L., Bland, R. D., Staub, N. C. 1975; 77 (4): 512-519

    Abstract

    In an attempt to further delineate the pathophysiology of the shock-lung syndrome, we studied the effect of hemorrhagic shock on the pulmonary microcirculation in the adult sheep with lung lymph flow and lymph protein transport as indices of fluid filtration and vascular permeability to protein. We noted that lymph flow remained at baseline levels during shock, despite significant decreases in pulmonary artery and left atrial pressures. This suggests that microvascular pressure is maintained by an increase in pulmonary venous resistance. We demonstrated that lymph protein transport does not increase during shock, which indicates that a change in pulmonary vascular permeability to protein does not occur.

    View details for Web of Science ID A1975V992200009

    View details for PubMedID 1145429

  • PREPARATION OF CHRONIC LUNG LYMPH FISTULAS IN SHEEP JOURNAL OF SURGICAL RESEARCH Staub, N. C., Bland, R. D., Brigham, K. L., Demling, R., ERDMANN, A. J., WOOLVERTON, W. C. 1975; 19 (5): 315-320

    View details for Web of Science ID A1975AX56400005

    View details for PubMedID 1195727

  • DISTRIBUTION VOLUMES OF [ALBUMIN-I-131, [SUCROSE-C-14, AND CL-36 IN SHEEP LUNG JOURNAL OF APPLIED PHYSIOLOGY Selinger, S. L., Bland, R. D., Demling, R. H., Staub, N. C. 1975; 39 (5): 773-779

    Abstract

    We measured the steady-state volumes of distribution for radioactive chloride, sucrose, and albumin in the lung of six anesthetized, spen-thorax sheep. We allowed 2 days for [131I]albumin to equilibrate throughout the body, 2 h for the 36Cl, and a 40-min constant infusion for [14C]sucrose before killing the animal. Five minutes before death, we gave [125I]albumin to tag lung plasma volume. We killed the animals by clamping both lung hila; we then removed the lungs and homogenized them. We measured residual red cell and plasma volume, total extravascular lung water, and the extravascular content of the three tracers. The distribution volumes expressed as fractions of blood-free lung weight were: 36Cl equals 0.44, sucrose equals 0.28, and albumin equals 0.07. If the sucrose distribution volume is taken as the best estimate of the lung's extravascular extracellular space, then chloride clearly overestimates the interstitial fluid volume, being either bound or partially intracellular. On the other hand, albumin clearly underestimates the interstitial fluid volume.

    View details for Web of Science ID A1975AX05100013

    View details for PubMedID 1102518

  • EARLY ALBUMIN INFUSION TO INFANTS AT RISK FOR RESPIRATORY DISTRESS ARCHIVES OF DISEASE IN CHILDHOOD Bland, R. D., Clarke, T. L., HARDEN, L. B., Meyer, J. L., RIES, J. P., MADDEN, W. A., CRAST, F. W., COYER, W. F., Bass, J. W. 1973; 48 (10): 800-805

    View details for Web of Science ID A1973R011500009

    View details for PubMedID 4749684

  • OTITIS MEDIA IN FIRST 6 WEEKS OF LIFE - DIAGNOSIS, BACTERIOLOGY, AND MANAGEMENT PEDIATRICS Bland, R. D. 1972; 49 (2): 187-?

    View details for Web of Science ID A1972L588500004

    View details for PubMedID 4551016

  • CORD-BLOOD TOTAL PROTEIN LEVEL AS A SCREENING AID FOR IDIOPATHIC RESPIRATORY-DISTRESS SYNDROME NEW ENGLAND JOURNAL OF MEDICINE Bland, R. D. 1972; 287 (1): 9-?

    View details for Web of Science ID A1972M873400003

    View details for PubMedID 5029231

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