Asthma is a chronic disorder of the airways that is characterized by airflow obstruction, inflammation, hyperreactivity and remodeling. Airway remodeling is, in part, due to increased smooth muscle cell growth, and immunomodulatory roles of airway smooth muscle cells have recently been recognized. Reactive oxygen species have been shown to serve as signaling mediators in airway smooth muscle cells. Mechanisms of how reactive oxygen species are involved in cell signaling events, however, remain largely undefined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat asthma. My long-range goal is to understand the mechanism of reactive oxygen species signaling in airway smooth muscle cells. The objective of this application is to evaluate the mechanism and functions of annexin A1 (lipocortin) carbonylation induced by mediators of asthma. The central hypothesis is that reactive oxygen species produced by mediators of asthma including platelet-derived growth factor (PDGF) and endothelin-1 promote carbonylation of annexin A1 (which regulates inflammation and cell growth) as a signal transduction mechanism. The hypothesis has been formulated on the basis of strong preliminary data in smooth muscle cells which suggest that: (i) PDGF and endothelin-1, important mediators of asthma, promote protein carbonylation;(ii) Mass spectrometry identified that annexin A1 (an anti-inflammatory, anti-proliferative and pro-apoptotic molecule), is one protein that is carbonylated;(iii) Annexin A1 interacts with proteins which promote proliferation and survival of smooth muscle cells and inflammatory responses;(iv) Overexpression of annexin A1 reduces smooth muscle cell number, (v) Carbonylation of annexin A1 is followed by proteasome- dependent degradation, and (vi) Iron chelation inhibits PDGF-induced upregulation of bcl-2 and interleukin-13 mRNA expression in human airway smooth muscle cells. Further, in vivo treatment of mice with allergens to induce asthma promoted degradation of annexin A1. The rationale for the proposed research is that, once knowledge of signaling pathways that regulate cell growth and inflammatory responses in airway smooth muscle cells has been obtained, it will lead to new strategies that can be used to prevent and/or treat asthma. The objective of the application will be accomplished by pursuing three specific aims: 1) Identify the mechanism of annexin A1 carbonylation by cell signaling mediators in human airway smooth muscle cells, 2) Determine the role of protein carbonylation in the mechanism of annexin A1 degradation, and 3) Define the roles of annexin A1 in the regulation of airway smooth muscle cell growth and inflammatory responses. The proposed work is innovative because it will investigate a novel mechanism for reactive oxygen species signaling and study the novel roles of annexin A1 in airway smooth muscle regulation for cell growth and inflammatory responses. It is my expectation that mediators of asthma including PDGF and endothelin-1 promote metal-catalyzed annexin A1 carbonylation that specifically influences cell growth, apoptotic and inflammatory signaling via mechanisms involving proteasomes. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions for asthma. In addition, the results will fundamentally advance the field of lung cell biology.

Public Health Relevance

Asthma is a chronic disorder of the airways that is characterized by airflow obstruction, inflammation, hyperreactivity and remodeling, which affects a large number of patients in the United States and worldwide. Airway smooth muscle cells which comprizes of airway walls play multifaceted role in the airway. Thus, understanding how airway smooth muscle cells are regulated should help developing effective therapeutic strategies for this condition. Oxygen free radicals have been shown to play important roles in regulating airway smooth muscle cells. This project is designed to identify detailed mechanisms of the actions of oxygen free radicals. Information generated in this project is expected to contribute to designing new therapeutic strategies for treating human asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-A (M1))
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Croxton, Thomas
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Georgetown University
Schools of Medicine
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