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Serpil C. Erzurum, M.D.Chair, Department of PathobiologyJoint Staff with Respiratory Institute Department of Pathobiology |
Research interests:
- Airway inflammation & Biology
- Reactive Oxygen and Nitrogen species in Lung Disease
- Pulmonary Vascular Endothelium and Angiogenesis
- Asthma; Pulmonary Hypertension
Research programs:
- Pathobiology of Asthma
- Redox Determinants of Severe Asthma
- Vasculopathy in Pulmonary Arterial Hypertension
The two major themes of research in our laboratory are the study of the airway biology of asthma and the vasculopathy that occurs in pulmonary arterial hypertension.
Asthma. We have focused on understanding the molecular mecha
nisms that initiate and maintain airway inflammation, and in particular the role of antioxidants and reactive oxygen (ROS) and nitrogen species (RNS) in the pathogenesis of asthmatic airway inflammation. The lungs produce high levels of nitric oxide (NO), which is detected in the exhaled air of healthy people and increased in exhaled air of asthmatics. Our studies identified that NO is produced continuously in the airway by the NO Synthase type 2 (NOS2). We found that asthmatic epithelium expresses much higher levels of NOS2 than normal airway epithelium. These findings have contributed to the use of exhaled NO as a biomarker of the inflammatory state of the airway. Current research is focused on understanding the regulatory pathways for NOS2 expression and activity, the post-translational modification of nitration (in particular nitration of antioxidant enzymes), and biologic consequences on airway remodeling events such as angiogenesis.
Pulmonary Arterial Hypertension (PAH). Abnormal vasculature characterized by disordered endothelial and smooth muscle cell proliferation is the hallmark of PAH. We have developed methods to culture primary pulmonary artery endothelial cells (PAEC) from PAH lungs (World Health Organization Class 1) at the time of explantation during lung transplant. Phenotypic characteristics of IPAH cells are distinctly different as compared to control cells. PAH endothelial cells have higher proliferative rates, resistance to apoptosis, activation of signal transduction and activator of transcription 3 (STAT3) pathway (a critical regulator of endothelial cell survival and angiogenesis), low levels of NO synthesis in part related to arginine substrate deficiency due to higher levels of arginase 2 (a metabolic checkpoint for endothelial cell proliferation), decreased mitochondrial numbers and reduced cellular respiration related to lower endothelial NO synthase activity, and greater glycolytic dependence for energy production. Current studies are aimed at understanding the processes that lead to the altered endothelial phenotype in PAH.
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Grant Awards:
- 2006 -11 NHLBI Program Project Grant: Pathobiology of Asthma National Institutes of Health
- 2006-11 American Heart Association Pulmonary Hypertension Breakthrough Initiative Transplant & Preparation Center
- 2006-11 NHLBI Severe Asthma Research Program network center
Key References :
Comhair SAA, Ricci KS, Arroliga M, Lara AR, Dweik RA, Song W, Hazen SL, Bleecker ER, Busse WW, Chung KF, Gaston B, Hastie A, Hew M, Jarjour N, Moore W, Peters S, Teague WG, Wenzel SE and Erzurum SC for the NHLBI Severe Asthma Research Program. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma. Am J Resp Crit Care Med. 2005;172:306-13. PDF
Ghosh S, Janocha AJ, Aronica MA, Swaidani S, Comhair SAA, Xu W, Zheng L, Kinter MT, Hazen SL, Erzurum SC. Nitrotyrosine Proteome Survey In Experimental Asthma Identifies Oxidative Modifications and Catalase Inactivation J Immunol. 2006 May 1;176(9):5587-97. PDF
Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RA, Stuehr DJ, Erzurum SC. Alterations of Cellular Bioenergetics in Pulmonary Artery Endothelial Cells. Proc Natl Acad Sci, USA 2007;104:1342-1347. PDF
Asosingh K, Swaidani S, Aronica M, Erzurum SC. Th1 and Th2 dependent endothelial progenitor cell recruitment and angiogenic switch in asthma. J Immunol. 2007 May 15;178(10):6482-94. PDF
Masri FA, Xu W, Comhair SAA, Asosingh K, Koo M, Vasanji A, Drazba J, Anand-Apte B, Erzurum SC. Proliferative Phenotype of Idiopathic Pulmonary Artery Hypertension Endothelial Cells. Am J Physiol Lung Cell Mol Physiol 2007 Sep;293(3):L548-54. PDF
Farha S, Asosingh K, Laskowski D, Licina L, Sekigushi H, Losordo DW, Dweik RA Wiedemann HP, Erzurum SC. Pulmonary Gas Transfer and Angiogenesis during the Menstrual Cycle. J Appl Physiol 2007 Nov;103(5):1789-95. PDF
Cannady SB, Batra PS, Leahy R, Citardi MJ, Janocha A, Ricci K, Comhair SAA, Wang Z, Hazen SL, Erzurum SC. Signal transduction and oxidative processes in sinonasal polyposis. J Allergy Clin Immunol 2007 Dec;120(6):1346-53. PDF
Erzurum SC, Ghosh S, Janocha AJ, Xu W, Bauer S, Bryan NS, Tejero J, Hemann C, Hille R, Stuehr DJ, Feelisch M. Beall CM. Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc Natl Acad Sci USA 2007 Nov 6;104(45):17593-8. PDF
Asosingh K, Aldred MA, Vasanji A, Drazba J, Sharp J, Farver C, Comhair SAA, Xu W, Licina L, Tuder RM, Erzurum SC. Increased Numbers of Circulating Proliferative CD34+CD133+ Multipotential Progenitor Cells in Idiopathic Pulmonary Arterial Hypertension. Am J Path. 2008 Mar;172(3):615-27. PDF
Lara A, Khatri SB, Wang Z, Comhair SA, Xu W, Dweik RA, Bodine M, Levison BS, Hammel J, Bleecker E, Busse W, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, Gaston B, Israel E, Jarjour N, Moore W, Peters SP, Teague WG, Wenzel S, Hazen SL, Erzurum SC. National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Alterations of the arginine metabolome in asthma. Am J Respir Crit Care Med. 2008 Oct 1;178(7):673-81. PDF
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