Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2015; 191 (11): 1273-1286
BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension
2015; 21 (4): 596-608
Pulmonary arterial hypertension is characterized by endothelial cell dysfunction, impaired BMPR2 signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates the development of hypoxic pulmonary hypertension in mice, but its potential to improve endothelial cell function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.To assess elafin-mediated regression of pulmonary vascular pathology in rats with pulmonary hypertension induced by VEGF receptor blockade and hypoxia (Sugen/Hypoxia), and in lung explants from pulmonary hypertension patients. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells from controls and patients, and to elucidate the underlying mechanism. Methods, Measurements and Main Results: In Sugen/Hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a product of BMPR2 signaling. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and in lung organ culture elafin decreased neointimal lesions. In normal and patient pulmonary artery endothelial cells, elafin enhanced survival and promoted angiogenesis by increasing pSMAD dependent and independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of caveolin-1 on endothelial surfaces.Elafin reverses obliterative changes in rat and human pulmonary arteries via elastase inhibition and caveolin-1 dependent amplification of BMPR2 signaling.
View details for DOI 10.1164/rccm.201412-2291OC
View details for Web of Science ID 000356105000014
View details for PubMedID 25853696
Complete resolution of idiopathic pulmonary arterial hypertension following chemotherapy.
European respiratory journal
2014; 43 (5): 1513-1515
Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension.
2014; 4: 4808-?
Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1? and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1?, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1?, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.
View details for DOI 10.1016/j.cmet.2015.03.010
View details for Web of Science ID 000352500800014
View details for PubMedID 25863249
Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?
BMC pulmonary medicine
2011; 11: 30-?
Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 ± 1.4?g/l) and CTEPH (4.3 ± 1.2?g/l) compared to control patients (3.4 ± 0.5?g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy.
View details for DOI 10.1038/srep04808
View details for PubMedID 24770447
Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2015; 35 (1): 146-154
Pulmonary hypertension (PH) is a life-threatening disease with poor prognosis. Encouraging efforts have been made to target the main vasoproliferative aspects of the disease. Promising emerging therapeutics are tyrosine kinase inhibitors such as imatinib.Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi-tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing.We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data.
View details for DOI 10.1186/1471-2466-11-30
View details for PubMedID 21605451
Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension.
Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
View details for DOI 10.1161/ATVBAHA.114.304364
View details for Web of Science ID 000346561100022
View details for PubMedID 25359856
Loss of Somatostatin Receptor Subtype 2 in Prostate Cancer Is Linked to an Aggressive Cancer Phenotype, High Tumor Cell Proliferation and Predicts Early Metastatic and Biochemical Relapse
2014; 9 (7)
N-terminal pro-brain natriuretic peptide is a useful prognostic marker in patients with pre-capillary pulmonary hypertension and renal insufficiency.
2014; 9 (4)
Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients' functional status and outcome. With a mean level of 242 ± 24 ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151 ± 18 ng/ml in 15 age- and gender-matched healthy subject (p = 0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r = 0.608, p < 0.001) and inversely with the 6-minute walking distance (r = -0.412, p = 0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p = 0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients' functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling.
View details for DOI 10.1007/s00408-015-9735-5
View details for PubMedID 25926293
The endothelial ADMA/NO pathway in hypoxia-related chronic respiratory diseases.
BioMed research international
2014; 2014: 501612-?
N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ?60 ml/min/1.73 m2) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m2). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r2?=?0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p?=?0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p?=?0.001) and survival (>2212 ng/l, p?=?0.047) in patients with renal insufficiency. Multivariate Cox's proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p?=?0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.
View details for DOI 10.1371/journal.pone.0094263
View details for PubMedID 24751887
Low intensity, long-term outpatient rehabilitation in COPD: a randomised controlled trial
Since its discovery, many adhere to the view that asymmetric dimethylarginine (ADMA), as an inhibitor of the synthesis of nitric oxide (NO), contributes to the pathogenesis of various diseases. Particularly, this is evident in disease of the cardiovascular system, in which endothelial dysfunction results in an imbalance between vasoconstriction and vasodilatation. Even if increased ADMA concentrations are closely related to an endothelial dysfunction, several studies pointed to a potential beneficial effect of ADMA, mainly in the context of angioproliferative disease such as cancer and fibrosis. Antiproliferative properties of ADMA independent of NO have been identified in this context. In particular, the regulation of ADMA by its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) is the object of many studies. DDAH is discussed as a promising therapeutic target for the indirect regulation of NO. In hypoxia-related chronic respiratory diseases, this controversy discussion of ADMA and DDAH is particularly evident and is therefore subject of this review.
View details for DOI 10.1155/2014/501612
View details for PubMedID 24719871
Characterization of Enterobacter cloacae Pneumonia: A Single-Center Retrospective Analysis
2011; 189 (6): 475-483
Most pulmonary rehabilitation programmes currently involve 2-3 sessions per week as recommended by international guidelines. We aimed to investigate whether relevant improvements in physical capabilities and quality of life in patients with chronic obstructive pulmonary disease (COPD) could be achieved by a long-term, low intensity, once weekly rehabilitation programme using limited resources.100 patients with moderate to severe COPD were randomised to a continuous outpatient interdisciplinary rehabilitation programme or standard care. Physiotherapy-led supervised outpatient training sessions were performed once weekly in addition to educational elements. Outcome measures at baseline and after 26 weeks were 6-minute-walk-test, cycle ergometry, and health-related quality of life.37 patients in the training group and 44 patients in the control group completed the study. After 26 weeks there were clinically significant differences between the groups for 6 minute-walk-distance (+59 m, 95% CI 28-89 m), maximum work load (+7.4 Watt, 95% CI 0.5-13.4 Watt) and St. George's Respiratory Questionnaire score (-5 points, 95% CI -10 to -1 points). Total staff costs of the programme per participant were????625.Clinically meaningful improvements in physical capabilities and health-related quality of life may be achieved using long-term pulmonary rehabilitation programmes of lower intensity than currently recommended.clinicaltrials.gov NCT01195402.
View details for DOI 10.1186/1465-9921-13-86
View details for Web of Science ID 000311558200001
View details for PubMedID 23017153
Molecular Basis of P2-Receptor-Mediated Calcium Signaling in Activated Pancreatic Stellate Cells
2011; 40 (5): 740-746
Enterobacter cloacae (E. cloacae) is a Gram-negative rod commonly found on intensive care units (ICU) causing severe infections with high mortality. Specific characteristics of E. cloacae pneumonia, however, have not been identified.Evaluation of clinical and microbiological records of patients with positive respiratory samples for E. cloacae was performed by a 1-year retrospective study in a large university hospital.Ninety-seven of 115 eligible patients with E. cloacae-positive respiratory samples developed pneumonia. Patients were predominantly male (68%), older (median age = 62 years), and immunodeficient (54%). Seventy-eight percent required ICU admission, of which 97% required mechanical ventilation. Ventilator-associated pneumonia (VAP) occurred in 58%. Those who developed E. cloacae VAP had undergone twice as many surgical procedures under translaryngeal intubation prior to VAP onset (89 vs. 48%, P < 0.0001). Overall, E. cloacae VAP mortality was 24%. In E. cloacae VAP patients, presence of translaryngeal tubes (P = 0.02) and female gender (P = 0.0003) were associated with poor survival. Multivariate analysis confirmed male sex as a protective factor (relative risk: 0.39; P = 0.007).Enterobacter cloacae causes VAP with high mortality, predominantly in women. Risk factors for E. cloacae pneumonia seem to match those for VAP. The presence of translaryngeal endotracheal tubes seems to be the specific factor for E. cloacae VAP.
View details for DOI 10.1007/s00408-011-9323-2
View details for Web of Science ID 000297350000006
View details for PubMedID 22009561
Fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation - a feasibility study
2011; 15 (4)
There is growing evidence that extracellular nucleotide-induced signaling confers to fibrogenesis in liver and pancreas. Pancreatic stellate cells (PSC) are the most important cell type in pancreatic fibrosis. P2 purine and pyrimidine receptors, again, are pivotal mediators of inflammatory and profibrogenic signals. Our aim was to elucidate the underlying signaling components in activated PSC.We performed expression analysis of calcium ion (Ca(2+)) signaling components and monitored real-time intracellular Ca(2+) responses to nucleotides in rat PSC.Adenosine monophosphate, adenosine diphosphate, and adenosine-5'-triphosphate elicited detectable rises in intracellular Ca(2+) concentrations. Stimulation of PSC by ATP led to intracellular Ca signals mediated through both P2X and P2Y receptors. Whereas uridine triphosphate-mediated Ca(2+) signals were generated by activation of P2Y receptors only, uridine diphosphate stimulated P2X receptors as well. Of the phospholipase C (PLC)/inositol-1,4,5-trisphosphate pathway, all PLC-facilitating G? subunits were present in activated cells as were all 3 inositol-1,4,5-trisphosphate receptor isoforms. In addition, transcripts of PLC-? and PLC-? isoforms were also strongly detectable.Activated PSC feature a plethora of elements from the Ca signaling toolkit and functionally express a subset of P2 nucleotide receptors. Purines and pyrimidines elicit robust intracellular Ca(2+) signals likely contributing to the fibrogenetic potential of these cells.
View details for DOI 10.1097/MPA.0b013e31821b5b68
View details for Web of Science ID 000291635800017
View details for PubMedID 21654543
Classification and Differential Diagnosis of Pulmonary Hypertension [German]
Atemwegs- und Lungenkrankheiten
2011; 37 (11): 443 - 448
Sweet taste receptor interacting protein CIB1 is a general inhibitor of InsP(3)-dependent Ca2+ release in vivo
JOURNAL OF NEUROCHEMISTRY
2008; 106 (5): 2249-2262
Noninvasive ventilation (NIV) is a standard procedure in selected patients with acute respiratory failure. Previous studies have used noninvasive ventilation to ensure adequate gas exchange during fiberoptic bronchoscopy in spontaneously breathing hypoxemic patients, thus avoiding endotracheal intubation. However, it is unknown whether bronchoscopy can be performed safely in patients with acute hypoxemic respiratory failure already in need of NIV prior to the decision for bronchoscopy.We prospectively investigated 40 consecutive, critically ill, adult patients with acute hypoxemic respiratory failure (14 women, 26 men, age 61 ± 15 years, partial pressure for oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 under noninvasive ventilation, Simplified Acute Physiology scores (SAPS II) 47 ± 9.9 points). All patients required noninvasive ventilation prior to the decision to perform bronchoscopy (median 10.5 h; range 2.2 to 114). Blood gases, heart rate, blood pressure and ventilation were monitored before, during and up to 120 minutes after bronchoscopy.Bronchoscopy could be completed in all patients without subsequent complications. Oxygen saturation fell to < 90% in two patients (5%), and the lowest value during the procedure was 84%. The mean PaO2/FiO2 ratio improved from 176 ± 54 at baseline to 240 ± 130 (P < 0.001) at the end of bronchoscopy and 210 ± 79 after 120 minutes. The transient mean partial pressure of carbon dioxide in the arterial blood (PaCO2) increase was 9.4 ± 8.1 mm Hg. Four patients (10%) required endotracheal intubation during the first eight hours after the procedure. Bronchoalveolar lavage yielded diagnostic information in 26 of 38 (68%) patients.In critically ill patients with acute hypoxemic respiratory failure requiring noninvasive ventilation, bronchoscopy can be performed with an acceptable risk. Since these patients per se have a high likelihood of subsequent endotracheal intubation due to failure of NIV, bronchoscopy should only be performed by experienced clinicians.
View details for DOI 10.1186/cc10328
View details for Web of Science ID 000298082800019
View details for PubMedID 21794138
In a search for sweet taste receptor interacting proteins, we have identified the calcium- and integrin-binding protein 1 (CIB1) as specific binding partner of the intracellular carboxyterminal domain of the rat sweet taste receptor subunit Tas1r2. In heterologous human embryonic kidney 293 (HEK293) cells, the G protein chimeras Galpha(16gust44) and Galpha(15i3) link the sweet taste receptor dimer TAS1R2/TAS1R3 to an inositol 1,4,5-trisphosphate (InsP3)-dependent Ca2+ release pathway. To demonstrate the influence of CIB1 on the cytosolic Ca2+ concentration, we used sweet and umami compounds as well as other InsP3-generating ligands in FURA-2-based Ca2+ assays in wild-type HEK293 cells and HEK293 cells expressing functional human sweet and umami taste receptor dimers. Stable and transient depletion of CIB1 by short-hairpin RNA increased the Ca2+ response of HEK293 cells to the InsP3-generating ligands ATP, UTP and carbachol. Over-expression of CIB1 had the opposite effect as shown for the sweet ligand saccharin, the umami receptor ligand monosodium glutamate and UTP. The CIB1 effect was dependent on the thapsigargin-sensitive Ca2+ store of the endoplasmic reticulum (ER) and independent of extracellular Ca2+. The function of CIB1 on InsP3-evoked Ca2+ release from the ER is most likely mediated by its interaction with the InsP3 receptor. Thus, CIB1 seems to be an inhibitor of InsP3-dependent Ca2+ release in vivo.
View details for DOI 10.1111/j.1471-4159.2008.05563.x
View details for Web of Science ID 000258360000023
View details for PubMedID 18627437