The overall goal of our Research Program is to identify the elements that initiate, intensify and modulate the inflammatory response in the asthmatic airway. Our Program is comprised of three highly synergistic Projects interconnected through the unifying hypothesis that asthma results from prolonged and active airway inflammation with failed attempts at resolution and repair leading to tissue destruction and remodeling. Projects are specifically aimed at defining mechanisms behind the well-established histopathology observed in asthmatic airways: injury and denudation of the airway epithelium (project 1), increased and aberrant deposition of extracellular matrix components (project 2), and airway injury through oxidative processes of eosinophils and neutrophils (project 3). The Research Program is comprehensive in that Projects will study the pro-inflammatory and inter-related roles of extracellular and cellular components, including leukocytes and resident smooth muscle and airway epithelial cells. Project 1 investigates how epithelial cells are active participants in inflammation through excessive nitric oxide synthesis, and downstream consequences of protein oxidation via exposure to NO-derived oxidants. Project 2 expands upon the pro-inflammatory role of resident cells, as it identifies how smooth muscle and epithelial cells participate in inflammation through synthesis of an extracellular hyaluronan matrix that is critical for recruitment/migration, proliferation, and activation of CD44 (+) leukocytes, e.g., monocytes/macrophages, mast cells, and eosinophils. Project 3 studies the oxidative processes mediated by key effector cells in asthma, eosinophils and neutrophils, and investigates whether or not oxidative products are useful as monitors of inflammation. Three scientific Cores (Clinical, Tissue Processing and Cell Culture, and Animal Model) and an Administrative Core significantly strengthen each Project and the overall Program by providing expertise, service, easy access to well-defined clinical samples and primary human cells in culture, and a murine allergen-induced airway inflammation asthma model, to all projects. Collectively the Projects, supported by Cores, allow our Program to comprehensively address fundamental mechanisms involved in the inflammatory processes leading to asthma clinical pathology, including acute exacerbations, chronic airway inflammation, and airway remodeling.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Noel, Patricia
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Dai, Yue; Haque, Mohammad Mahfuzul; Stuehr, Dennis J (2017) Restricting the conformational freedom of the neuronal nitric-oxide synthase flavoprotein domain reveals impact on electron transfer and catalysis. J Biol Chem 292:6753-6764
Ghosh, Arnab; Stuehr, Dennis J (2017) Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. Antioxid Redox Signal 26:182-190
Xu, Weiling; Comhair, Suzy A A; Janocha, Allison J et al. (2017) Arginine metabolic endotypes related to asthma severity. PLoS One 12:e0183066
Kartha, Ganesh K; Li, Ina; Comhair, Suzy et al. (2017) Co-Occurrence of Asthma and Nephrolithiasis in Children. PLoS One 12:e0168813
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Zein, Joe G; Love, Thomas E; Erzurum, Serpil C (2017) Asthma Is Associated with a Lower Risk of Sepsis and Sepsis-related Mortality. Am J Respir Crit Care Med 196:787-790
Jang, Eunjung; Nguyen, Quang Tam; Kim, Sohee et al. (2017) Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation. J Immunol 199:3943-3951
Hwangbo, Cheol; Lee, Heon-Woo; Kang, Hyeseon et al. (2017) Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension. Circulation 135:2288-2298
Stober, Vandy P; Johnson, Collin G; Majors, Alana et al. (2017) TNF-stimulated gene 6 promotes formation of hyaluronan-inter-?-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. J Biol Chem 292:20845-20858
Ghosh, Arnab; Koziol-White, Cynthia J; Asosingh, Kewal et al. (2016) Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proc Natl Acad Sci U S A 113:E2355-62

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