Publications

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  • Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis HAEMATOLOGICA Gars, E., Purington, N., Scott, G., Chisholm, K., Gratzinger, D., Martin, B. A., Ohgami, R. S. 2018; 103 (10): 1635–41
  • Flow Immunophenotyping of Benign Lymph Nodes Sampled by FNA: Representative With Diagnostic Pitfalls. Cancer cytopathology Scott, G. D., Lau, H. D., Kurzer, J. H., Kong, C. S., Gratzinger, D. A. 2018

    Abstract

    BACKGROUND: Fine-needle aspiration with flow cytometry (FNA-FC) is routinely used in the evaluation of lymph nodes suspicious for lymphoma, yet data comparing immunophenotype distributions and outliers in benign lymph nodes sampled by fine-needle aspiration (FNA) versus excision are lacking.METHODS: Flow cytometry data from 289 benign lymph node FNA cases were assessed for the overall antigen distribution, with a focus on outliers relevant to the diagnosis of lymphoma. Distributions and outlier proportions were compared with those of a separate cohort of 298 excisional biopsies.RESULTS: Compared with excisional biopsies, FNA specimens overrepresented CD3+ events (72% vs 63%), underrepresented CD19+ events (22% vs 29%), and had 25% fewer large cell-gated events. Normalized antigen distributions in FNA were equivalent to those in excisional biopsy. Twenty-three percent of FNA-FC cases exhibited an outlier, including a skewed kappa:lambda light-chain ratio, increased CD5+ or CD10+ B-cell events, a skewed CD4:CD8 ratio, and increased CD7 loss on T cells, with no significant differences in frequency or type in comparison with excisional specimens. Outliers for the light-chain ratio and T-cell antigens were enriched among older patients and included patients with a variety of autoimmune/rheumatologic conditions.CONCLUSIONS: Benign lymph node FNA yields flow immunophenotypes remarkably similar to those from excisional biopsies. Outlier flow immunophenotypes are identified in benign lymph nodes sampled by FNA at a frequency similar to that with excisional biopsies. Older patients, who have a higher baseline risk of lymphoma, are more likely to exhibit lymphoma-mimicking outliers such as a light-chain predominance on B cells and skewed CD4:CD8 ratios or increased CD7 loss on T cells, and they warrant additional diagnostic caution.

    View details for PubMedID 30194715

  • Eosinophils increase airway sensory nerve density in mice and in human asthma SCIENCE TRANSLATIONAL MEDICINE Drake, M. G., Scott, G. D., Blum, E. D., Lebold, K. M., Nie, Z., Lee, J. J., Fryer, A. D., Costello, R. W., Jacoby, D. B. 2018; 10 (457)

    Abstract

    In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects. Increased innervation was associated with a lack of bronchodilator responsiveness and increased irritant sensitivity. In a mouse model of eosinophilic airway inflammation, the increase in nerve density and airway hyperresponsiveness were mediated by eosinophils. Our results implicate airway nerve remodeling as a key mechanism for increased irritant sensitivity and exaggerated airway responsiveness in eosinophilic asthma.

    View details for PubMedID 30185653

  • Flow Immunophenotyping of Benign Lymph Nodes Sampled by FNA: Representative With Diagnostic Pitfalls CANCER CYTOPATHOLOGY Scott, G. D., Lau, H. D., Kurzer, J. H., Kong, C. S., Gratzinger, D. A. 2018; 126 (9): 797–808

    View details for DOI 10.1002/cncy.22038

    View details for Web of Science ID 000454533300007

  • Immunophenotype signatures for Kikuchi's Disease, Castleman's Disease, and Angiomyomatous Hamartoma: rare diseases drawn out of large-scale normative data using an informatics approach Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 550
  • Large-scale flow immunophenotyping of benign lymph nodes sampled by fine needle aspiration: representative specimens with diagnostic pitfalls Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 173
  • Immunophenotype signatures for Kikuchi's Disease, Castleman's Disease, and Angiomyomatous Hamartoma: rare diseases drawn out of large-scale normative data using an informatics approach Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 550
  • Large-scale flow immunophenotyping of benign lymph nodes sampled by fine needle aspiration: representative specimens with diagnostic pitfalls Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 173
  • Defining Normal: Flow Cytometry Immunophenotyping of Benign Lymph Nodes Sampled by Fine Needle Aspiration or Surgical Biopsy Scott, G., Gratzinger, D. OXFORD UNIV PRESS INC. 2018: S85
  • Interfacing Complex Laboratory Instruments during a Change to Epic Beaker. Journal of pathology informatics Scott, G. D., Schrandt, C., Ho, C. C., Chung, M. C., Zhou, D., Shi, R. Z. 2018; 9: 24

    Abstract

    Background: Implementing a laboratory-developed test sometimes requires incorporating an unconventional device into the laboratory information system (LIS) and customizing an interface to reduce transcription error and improve turnaround time. Such a custom interface is a necessity for complicated high-volume tests such as 25-OH Vitamin D by liquid chromatography-tandem mass spectrometry (LC-MS/MS) when there is no vendor-or LIS-supplied interface available. Here, we describe our work and experience interfacing a API 5000 LC-MS/MS instrument with our newly implemented LIS, Epic Beaker, using a combination of in-house scripting software and a middleware vendor, Data Innovations.Materials and Methods: For input interfacing, custom scripting software was developed to transcribe batched order lists generated by Epic into files usable by the instrument software, Analyst. For output interfacing, results from the LC-MS/MS system were fed to a unidirectional instrument driver made by Data Innovations and selected data were transferred to the LIS.Results: Creation and validation of a new driver by Data Innovations took approximately 6 months. The interface was adopted for 25-OH Vitamin D and testosterone testing during periods of increasing test volume (4.5-fold over 8 years and 1.25-fold over 5 years). The amount of time spent reporting 25-OH Vitamin D results decreased 82% per order resulting in a savings of 1370 technician work hours and the amount of time spent reporting testosterone results decreased 75% per order resulting in a savings of 400 technician work hours.Conclusions: A mixed model using custom scripting and curated commercial middleware serve as a durable interface solution for laboratory instrumentation such as an LC-MS/MS and are flexible to future changes in instrument software, networking protocols, and the scope of LISs and work area managers.

    View details for PubMedID 30034922

  • The impact of postoperative therapy on primary cardiac sarcoma. The Journal of thoracic and cardiovascular surgery Wu, Y., Million, L., Moding, E. J., Scott, G., Berry, M., Ganjoo, K. N. 2018; 156 (6): 2194–2203

    Abstract

    Primary cardiac sarcomas (PCS) are extremely rare, portend a very poor prognosis, and have limited outcomes data to direct management. This study evaluated the impact of postoperative chemotherapy and/or radiotherapy on survival for PCS.A retrospective chart review was conducted of 12 patients diagnosed with and who underwent resection for PCS at a single institution between 2000 and 2016. Data were collected on patient/tumor characteristics and analyzed with respect to treatment and outcome using Kaplan-Meier methods.Median age was 43 (range 21-73 years) with a 50:50 male-to-female ratio. The most common subtype was angiosarcoma (42%), and 25% presented with distant metastases (DMs). The initial treatment modality for all patients was surgery, with 58% having macroscopically positive (R2) margins. In total, 75% received postoperative chemotherapy and/or radiotherapy. Median progression-free survival (PFS) was 5.9 months, and median overall survival (OS) was 12.0 months. Achieving negative or microscopically positive margins (R0/R1) as compared with R2 resection significantly improved PFS (12.6 vs 2.7 months, P = .008) and OS (21.8 vs 7.2 months, P = .006). DM at presentation demonstrated a significantly shorter OS (7.0 vs 16.9 months, P = .04) and PFS (0.7 vs 7.9 months, P = .003) compared with localized disease. Patients given postoperative therapy had longer OS compared with surgery only, but this difference was not statistically significant (15.5 vs 2.6 months, P = .12).Gross total surgical resection can significantly improve PFS and OS in PCS, but DM at diagnosis is an extremely poor prognostic sign. Postoperative therapy should be considered, although this study was likely underpowered to demonstrate a statistically significant benefit.

    View details for PubMedID 30454911

  • The Impact of Post-Operative Therapy on Primary Cardiac Sarcoma The Journal of Thoracic and Cardiovascular Surgery Wu, Y., Million, L., Moding, E. J., Scott, G., Berry, M., Ganjoo, K. N. 2018
  • Bone marrow histomorphologic criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica Gars, E., Purington, N., Scott, G., Chisholm, K., Gratzinger, D., Martin, B. A., Ohgami, R. S. 2018

    Abstract

    Hemophagocytic lymphohistiocytosis is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH-2004 trial. Hemophagocytosis is the only histomorphologic criterion, but in isolation is neither specific nor sensitive for the diagnosis of hemophagocytic lymphohistiocytosis. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphologic evidence of hemophagocytosis in hemophagocytic lymphohistiocytosis have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphologic hemophagocytosis could be identified, and if such criteria would aid in the diagnosis of hemophagocytic lymphohistiocytosis. We analyzed the morphologic features of hemophagocytosis in 78 patients presenting with clinical features suspicious for hemophagocytic lymphohistiocytosis: 40 patients with hemophagocytic lymphohistiocytosis and 38 patients without hemophagocytic lymphohistiocytosis. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes (1 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.86, 0.99), nucleated erythrocytes (4 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (area under the curve: 0.91, 95% confidence interval: 0.85, 0.95) are strongly associated with hemophagocytic lymphohistiocytosis. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively distinguished between hemophagocytic lymphohistiocytosis and non-hemophagocytic lymphohistiocytosis (cross-validated area under curve: 0.90, 95% confidence interval: 0.83, 0.97).

    View details for PubMedID 29903767

  • Lymphatic Malformation Occurring Within The Lateral Ventricle: A Case Report Lummus, S., Scott, G., Cheshier, S., Born, D. OXFORD UNIV PRESS INC. 2017: 542
  • Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy. Journal of clinical pathology Scott, G. D., Atwater, S. K., Gratzinger, D. A. 2017

    Abstract

    To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers.Clinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course.We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma.Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.

    View details for DOI 10.1136/jclinpath-2017-204687

    View details for PubMedID 28916595

  • Epidermotropic metastasis of primary lung adenocarcinoma. Journal of cutaneous pathology Scott, G. D., Kwong, B. Y., Novoa, R. A. 2016; 43 (9): 798-801

    Abstract

    Cutaneous metastasis of lung cancer is a rare event and usually portends a grim prognosis. Several cases of lung cancer with cutaneous metastasis have been reported, but these have been largely limited to the dermis. Here we describe a unique case of cutaneous metastatic lung adenocarcinoma largely limited to the epidermis, mimicking Paget's disease or a cutaneous adnexal tumor.

    View details for DOI 10.1111/cup.12741

    View details for PubMedID 27234927

  • Human and Mouse Eosinophils Have Antiviral Activity against Parainfluenza Virus AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Drake, M. G., Bivins-Smith, E. R., Proskocil, B. J., Nie, Z., Scott, G. D., Lee, J. J., Lee, N. A., Fryer, A. D., Jacoby, D. B. 2016; 55 (3): 387-394

    Abstract

    Respiratory viruses cause asthma exacerbations. Because eosinophils are the prominent leukocytes in the airways of 60-70% of patients with asthma, we evaluated the effects of eosinophils on a common respiratory virus, parainfluenza 1, in the lung. Eosinophils recruited to the airways of wild-type mice after ovalbumin sensitization and challenge significantly decreased parainfluenza virus RNA in the lungs 4 days after infection compared with nonsensitized animals. This antiviral effect was also seen in IL-5 transgenic mice with an abundance of airway eosinophils (NJ.1726) but was lost in transgenic eosinophil-deficient mice (PHIL) and in IL-5 transgenic mice crossed with eosinophil-deficient mice (NJ.1726-PHIL). Loss of the eosinophil granule protein eosinophil peroxidase, using eosinophil peroxidase-deficient transgenic mice, did not reduce eosinophils' antiviral effect. Eosinophil antiviral mechanisms were also explored in vitro. Isolated human eosinophils significantly reduced parainfluenza virus titers. This effect did not involve degradation of viral RNA by eosinophil granule RNases. However, eosinophils treated with a nitric oxide synthase inhibitor lost their antiviral activity, suggesting eosinophils attenuate viral infectivity through production of nitric oxide. Consequently, eosinophil nitric oxide production was measured with an intracellular fluorescent probe. Eosinophils produced nitric oxide in response to virus and to a synthetic agonist of the virus-sensing innate immune receptor, Toll-like receptor (TLR) 7. IFNγ increased expression of eosinophil TLR7 and potentiated TLR7-induced nitric oxide production. These results suggest that eosinophils promote viral clearance in the lung and contribute to innate immune responses against respiratory virus infections in humans.

    View details for DOI 10.1165/rcmb.2015-0405OC

    View details for Web of Science ID 000385984100009

    View details for PubMedID 27049514

    View details for PubMedCentralID PMC5023029

  • Presumed Second Focus of Lung Immunoglobulin G4-Related Disease Found to be Adenocarcinoma ANNALS OF THORACIC SURGERY Scott, G. D., Sauer, D. A., Woolf, K. M., Sukumar, M. S., Tieu, B. H. 2016; 101 (5): 1965-1967

    Abstract

    We describe a patient presenting with bilateral radiologically similar lung lesions initially diagnosed as immunoglobulin (Ig) G4-related disease from biopsy of one lesion, but radiographic changes 6 months later prompted biopsy of the second lesion and showed adenocarcinoma. No case of lung IgG4-related disease and a distant lung malignancy has been previously reported. This is notable because lung IgG4-related disease often manifests in multiple thoracic locations but is diagnosed from a representative biopsy specimen.

    View details for DOI 10.1016/j.athoracsur.2015.07.041

    View details for PubMedID 27106428

  • New-onset cutaneous lichen planus following therapy for hepatitis C with ledipasvir-sofosbuvir JOURNAL OF CUTANEOUS PATHOLOGY Scott, G. D., Rieger, K. E. 2016; 43 (4): 408–9

    View details for PubMedID 26816004

  • Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Lee, J. J., Protheroe, C. A., Luo, H., Ochkur, S. I., Scott, G. D., Zellner, K. R., Raish, R. J., Dahl, M. V., Vega, M. L., Conley, O., Condjella, R. M., Kloeber, J. A., Neely, J. L., Patel, Y. S., Maizer, P., Mazzolini, A., Fryer, A. D., Jacoby, N. W., Jacoby, D. B., Lee, N. A. 2015; 135 (2): 477-U643

    Abstract

    Contact toxicant reactions are accompanied by localized skin inflammation and concomitant increases in site-specific itch responses. The role(s) of eosinophils in these reactions is poorly understood. However, previous studies have suggested that localized eosinophil-nerve interactions at sites of inflammation significantly alter tissue innervation.To define a potential mechanistic link between eosinophils and neurosensory responses in the skin leading to itching.BALB/cJ mice were exposed to different contact toxicants, identifying trimellitic anhydride (TMA) for further study on the basis of inducing a robust eosinophilia accompanied by degranulation. Subsequent studies using TMA were performed with wild type versus eosinophil-deficient PHIL mice, assessing edematous responses and remodeling events such as sensory nerve innervation of the skin and induced pathophysiological responses (ie, itching).Exposure to TMA, but not dinitrofluorobenzene, resulted in a robust eosinophil skin infiltrate accompanied by significant levels of degranulation. Follow-up studies using TMA with wild type versus eosinophil-deficient PHIL mice showed that the induced edematous responses and histopathology were, in part, causatively linked with the presence of eosinophils. Significantly, these data also demonstrated that eosinophil-mediated events correlated with a significant increase in substance P content of the cutaneous nerves and an accompanying increase in itching, both of which were abolished in the absence of eosinophils.Eosinophil-mediated events following TMA contact toxicant reactions increase skin sensory nerve substance P and, in turn, increase itching responses. Thus, eosinophil-nerve interactions provide a potential mechanistic link between eosinophil-mediated events and neurosensory responses following exposure to some contact toxicants.

    View details for DOI 10.1016/j.jaci.2014.07.003

    View details for PubMedID 25129680

  • Tissue Optical Clearing, Three-Dimensional Imaging, and Computer Morphometry in Whole Mouse Lungs and Human Airways AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Scott, G. D., Blum, E. D., Fryer, A. D., Jacoby, D. B. 2014; 51 (1): 43-55

    Abstract

    In whole adult mouse lung, full identification of airway nerves (or other cellular/subcellular objects) has not been possible due to patchy distribution and micron-scale size. Here we describe a method using tissue clearing to acquire the first complete image of three-dimensional (3D) innervation in the lung. We then created a method to pair analysis of nerve (or any other colabeled epitope) images with identification of 3D tissue compartments and airway morphometry by using fluorescent casting and morphometry software (which we designed and are making available as open-source). We then tested our method to quantify a sparse heterogeneous nerve population by examining visceral pleural nerves. Finally, we demonstrate the utility of our method in human tissue to image full thickness innervation in irregular 3D tissue compartments and to quantify sparse objects (intrinsic airway ganglia). Overall, this method can uniquely pair the advantages of whole tissue imaging and cellular/subcellular fluorescence microscopy.

    View details for DOI 10.1165/rcmb.2013-0284OC

    View details for PubMedID 24471696

  • Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex FRONTIERS IN HUMAN NEUROSCIENCE Scott, G. D., Karns, C. M., Dow, M. W., Stevens, C., Neville, H. J. 2014; 8

    Abstract

    Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl's gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11-15° vs. 2-7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl's gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl's gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf adults.

    View details for DOI 10.3389/fnhum.2014.00177

    View details for PubMedID 24723877

  • Toll-like Receptor 7 Rapidly Relaxes Human Airways AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Drake, M. G., Scott, G. D., Proskocil, B. J., Fryer, A. D., Jacoby, D. B., Kaufman, E. H. 2013; 188 (6): 664-672

    Abstract

    Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs.To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs.Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs.The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways.TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.

    View details for DOI 10.1164/rccm.201303-0442OC

    View details for PubMedID 23924358

  • Quantifying Nerve Architecture in Murine and Human Airways Using Three-Dimensional Computational Mapping AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Scott, G. D., Fryer, A. D., Jacoby, D. B. 2013; 48 (1): 10-16

    Abstract

    The quantitative histological analysis of airway innervation using tissue sections is challenging because of the sparse and patchy distribution of nerves. Here we demonstrate a method using a computational approach to measure airway nerve architecture that will allow for more complete nerve quantification and the measurement of structural peripheral neuroplasticity in lung development and disease. We demonstrate how our computer analysis outperforms manual scoring in quantifying three-dimensional nerve branchpoints and lengths. In murine lungs, we detected airway epithelial nerves that have not been previously identified because of their patchy distribution, and we quantified their three-dimensional morphology using our computer mapping approach. Furthermore, we show the utility of this approach in bronchoscopic forceps biopsies of human airways, as well as the esophagus, colon, and skin.

    View details for DOI 10.1165/rcmb.2012-0290MA

    View details for PubMedID 23103997

  • Role of parasympathetic nerves and muscarinic receptors in allergy and asthma. Chemical immunology and allergy Scott, G. D., Fryer, A. D. 2012; 98: 48-69

    Abstract

    Parasympathetic nerves control the symptoms and inflammation of allergic diseases primarily by signaling through peripheral muscarinic receptors. Parasympathetic signaling targets classic effector tissues such as airway smooth muscle and secretory glands and mediates acute symptoms of allergic disease such as airway narrowing and increased mucus secretion. In addition, parasympathetic signaling modulates inflammatory cells and non-neuronal resident cell types such as fibroblasts and smooth muscle contributing to chronic allergic inflammation and tissue remodeling. Importantly, muscarinic antagonists are experiencing a rebirth for the treatment of asthma and may be useful for treating other allergic diseases.

    View details for DOI 10.1159/000336498

    View details for PubMedID 22767057

  • Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis JOURNAL OF EXPERIMENTAL MEDICINE Braun, T. P., Zhu, X., Szumowski, M., Scott, G. D., Grossberg, A. J., Levasseur, P. R., Graham, K., Khan, S., Damaraju, S., Colmers, W. F., Baracos, V. E., Marks, D. L. 2011; 208 (12): 2449-2463

    Abstract

    Skeletal muscle catabolism is a co-morbidity of many chronic diseases and is the result of systemic inflammation. Although direct inflammatory cytokine action on muscle promotes atrophy, nonmuscle sites of action for inflammatory mediators are less well described. We demonstrate that central nervous system (CNS)-delimited interleukin 1β (IL-1β) signaling alone can evoke a catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic-pituitary-adrenal (HPA) axis activation, as CNS IL-1β-induced atrophy is abrogated by adrenalectomy. Furthermore, we identified a glucocorticoid-responsive gene expression pattern conserved in models of acute and chronic inflammatory muscle atrophy. In contrast with studies suggesting that the direct action of inflammatory cytokines on muscle is sufficient to induce catabolism, adrenalectomy also blocks the atrophy program in response to systemic inflammation, demonstrating that glucocorticoids are requisite for this process. Additionally, circulating levels of glucocorticoids equivalent to those produced under inflammatory conditions are sufficient to cause profound muscle wasting. Together, these data suggest that a significant component of inflammation-induced muscle catabolism occurs indirectly via a relay in the CNS.

    View details for DOI 10.1084/jem.20111020

    View details for PubMedID 22084407

  • Role of TNF-alpha in virus-induced airway hyperresponsiveness and neuronal M-2 muscarinic receptor dysfunction BRITISH JOURNAL OF PHARMACOLOGY Nie, Z., Scott, G. D., Weis, P. D., Itakura, A., Fryer, A. D., Jacoby, D. B. 2011; 164 (2B): 444-452

    Abstract

    Infections with respiratory viruses induce exacerbations of asthma, increase acetylcholine release and potentiate vagally mediated bronchoconstriction by blocking inhibitory M₂ muscarinic receptors on parasympathetic neurons. Here we test whether virus-induced M₂ receptor dysfunction and airway hyperresponsiveness are tumour necrosis factor-alpha (TNF-α) dependent.Guinea pigs were pretreated with etanercept or phosphate-buffered saline 24 h before intranasal infection with parainfluenza. Four days later, pulmonary inflation pressure, heart rate and blood pressure were measured. M₂ receptor function was assessed by the potentiation by gallamine (an M₂ receptor antagonist) of bronchoconstriction caused by electrical stimulation of the vagus nerves and measured as increased pulmonary inflation pressure. Human airway epithelial cells were infected with influenza and TNF-α concentration in supernatant was measured before supernatant was applied to human neuroblastoma cells. M₂ receptor expression in these neuroblastoma cells was measured by qRT-PCR.Influenza-infected animals were hyperresponsive to vagal stimulation but not to intravenous ACh. Gallamine did not potentiate vagally induced bronchoconstriction in virus-infected animals, indicating M₂ receptor dysfunction. Etanercept prevented virus-induced airway hyperresponsiveness and M₂ receptor dysfunction, without changing lung viral titres. Etanercept caused a non-significant decrease in total cells, macrophages and neutrophils in bronchoalveolar lavage. Influenza infection significantly increased TNF-α release from isolated epithelial cells, sufficient to decrease M₂ receptors in neuroblastoma cells. This ability of supernatants from infected epithelial cells to inhibit M₂ receptor expression was blocked by etanercept.TNF-α is a key mediator of virus-induced M₂ muscarinic receptor dysfunction and airway hyperresponsiveness.

    View details for DOI 10.1111/j.1476-5381.2011.01393.x

    View details for PubMedID 21457223