Serpil C. Erzurum, M.D.
Staff

Pulmonary and Critical Care Medicine/Cancer Biology
Cleveland Clinic Foundation/NB40
9500 Euclid Avenue
Cleveland, Ohio 44195
Telephone : (216) 445-5764
Fax : (216) 445-6269
erzurus@ccf.org

Airway inflammation, Airway epithelial biology, Reactive oxygen and Nitrogen species, Asthma, Pulmonary hypertension.

Current program:

• Mechanisms of Inflammation in Asthmatic Airway Epithelium
• Nitric oxide production and reactions in the lung
• Antiviral host defense in the lung

Investigators:

• Baaklini, Marcelle, B.S.
• Comhair, Suzy A.A. , Ph.D.
• Ghosh, Sudakshina, Ph.D.
• Goggans, Tannishia, B.A.
• Janocha, Allison, B.A.
• Laskowski, Daniel, RP.F.T.
• Masri, Fares, B.A.
• Pyle, Jacqueline, R.N.
• Ricci, Kristen, B.S.
• Szabo, Katalin, B.S.
• Xu, Weiling, Ph.D.

Collaborators:

• Aronica, Mark, M.D., Pulmonary and Critical Care Medicine, CCF
• Arroliga, Alejandro, M.D., Pulmonary Allergy and Critical Care Medicine, CCF
• Beall, Cynthia, Ph.D., Anthropology, Case Western Reserve University
• Dweik, Raed, M.D., Pulmonary, Allergy and Critical Care Medicine, CCF
• Haque, Jaharul, Ph.D., Department of Cancer Biology, CCF
• Hascall, Vince, Ph.D., Department of Biomedical Engineering, CCF
• Hazen, Stan, M.D., Ph.D., Department of Cell Biology, CCF
• Hsieh, Fred, M.D., Department of Pulmonary, Allergy and Critical Care Medicine, CCF
• Stuehr, Dennis, Ph.D., Department of Immunology, CCF
• Williams, Bryan R.G., Ph.D., Department of Cancer Biology, CCF

Brief Description:

Our laboratory studies the molecular   mechanisms that initiate and maintain   airway inflammation, and has focused on the role of antioxidants and reactive oxygen (ROS) and nitrogen species (RNS) in the pathogenesis of inflammation. The lungs have been shown to produce significant amounts of reactive nitrogen species, i.e., nitric oxide (NO). NO is present in the exhaled air of normal individuals and is increased in exhaled air of asthmatic individuals. While excessive NO may be an injurious oxidant species, NO is endogenously produced in healthy human lungs, suggesting it has a physiologic role. Three isoforms of nitric oxide synthase (NOS), the enzymes responsible for endogenous NO production, have been described in cells: inducible NOS (NOS2) and two isoforms of constitutive NOS (NOS1 and 3). Expression of NOS2 has traditionally been found in cells stimulated by inflammatory cytokines such as interleukin-1 beta (IL-1 b ), tumor necrosis factor-alpha (TNF- a ), and interferon gamma (IFN- g ). However, we have identified and cloned the NOS isoform from freshly obtained healthy human airway epithelium and have found that this continuously expressed airway NOS is NOS2. This was the first conclusive demonstration of continuous expression of the NOS2 gene in normal non-inflamed tissues and suggests unique mechanisms for regulation of NOS2 in airway epithelial cells. Increased expression of the NOS2 gene may contribute to the pathogenesis of inflammatory airway diseases, i.e. asthma and bronchitis. We found that asthmatic epithelium expresses much higher levels of NOS2 than normal airway epithelium. In contrast, decreased NO may also lead to lung disease. We have recently demonstrated that individuals with primary pulmonary hypertension have decreased levels of NO in comparison to healthy controls. Thus, airway epithelial NOS2 may contribute to pulmonary vascular response by generating NO, which is pharmacologically defined as a potent vasodilator. NO also serves an innate host defense role, and we have shown that loss of NOS2 in Cystic Fibrosis airways contributes to the susceptibility of airways to virus infection. Our current work is concentrated on studying the source, regulation and role of NO in the lung, with the long-term goal of determining how NO and reactive oxygen species are mechanistically involved in lung diseases to design effective therapies.

Key References:

Guo FH, DeRaeve H, Rice TW, Stuehr D, Thunnissen FBJM, Erzurum SC Ciontinuous NO synthesis by inducible nitric oxide synthase in normal human airways in vivo. Proc Natl Acad Sci 1995; 92:7809-7813.

Guo FH, Uetani K, Haque J, Williams BRG, Dweik RA, Thunnisen F, Calhoun W, Erzurum SC.   Interferon g and Interleukin-4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators.   J Clin Invest 1997;100:829-838.

Dweik RA, Laskowski D, Abu-Soud HM, Kaneko FT, Hutte R, Stuehr DJ, Erzurum SC.   Nitric oxide synthesis in the lung:   regulation by oxygen through a kinetic mechanism.   J Clin Invest 1998;101:660-666.

Comhair SAA, Bhathena PR,   Dweik RA, Kavuru MS, Erzurum SC. Rapid Loss of Superoxide Dismutase Activity during Antigen-Induced Asthmatic Response.   Lancet 2000;355:624.

Guo FH, Comhair SAA, Zheng S, Dweik RA, Eissa NT, Thomassen MJ, Calhoun W, Erzurum SC.   Molecular Mechanisms of Increased Nitric Oxide (NO) in Asthma: Evidence for Transcriptional and Post-translational Regulation of NO Synthesis. J Immunol 2000;164:5970-5980.

Comhair SAA, Bhathena PR, Farver C, Thunnissen FBJM, Erzurum SC.   Extracellular Glutathione Peroxidase Induction in Asthmatic Lungs: Evidence for Redox Regulation of Expression in Human Airway Epithelial Cells. Faseb J 2001;15:70-78.

Dweik RA, Comhair SAA, Gaston B, Thunnissen FBJM, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. Nitric Oxide Chemical Events in the Human Airway During the Immediate and Late Antigen Induced Asthmatic Response.   Proc Natl Acad Sci USA 2001;98:2622-2627.

Beall C, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, Alarcon AM, Gonzales C, Erzurum SC. Pulmonary nitric oxide in mountain dwellers: populations living at high altitudes have an adaptive mechanism to offset hypoxia.   Nature 2001;414:411-412.

Zheng, S, De BP, Choudhary S, Comhair SAA, Pilewski J, Haque SJ, Erzurum, SC. Impaired Innate Host Defense causes susceptibility to respiratory virus infections in cystic fibrosis.   Immunity 2003; 18: 619-630.