Cigarette Smoke-Induced Cyclooxygenase-2 Expression in Human Tracheal Smooth Muscle Cells

Inflammation is a hallmark of all major airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). The elevated expression of various inflammatory proteins such as adhesion molecules, cyclooxygenase enzymes and their products, cytokines, and proteases in experimental and clinical airway diseases, and intervention studies in experimental animals suggest that several of these inflammatory target proteins contribute to pulmonary diseases. Most notably, cigarette smoke (CS) has been implicated in airway inflammation. The inflammatory mechanisms underlying the expression of these inflammatory proteins may contribute to tissue remodeling and inflammatory progress. Recently, oxidative stress due to generation of ROS (e.g. mitochondrial dysfunction and NADPH oxidase activation) may be involved in lung injury and inflammation. ROS can also be sensed by the cells and trigger intracellular signaling cascades potentiating chronic inflammation. Interplay between ROS and inflammatory proteins induced by proinflammatory mediators leading to airway inflammation remains largely unknown. Moreover, we have demonstrated that IL-1and TNF-may act as pro-inflammatory factors and induce expression of cPLA2, COX-2, adhesion molecules, and matrix metalloproteinase-9 (MMP-9). COX-2 and its product PGE2 may promote the pathogenesis of various lung injuries and airway inflammation. Therefore, we hypothesize that CS-initiated airway inflammation is mediated by the generation of ROS and the induction of inflammatory protein COX-2 assocaited with PGE2 synthesis in tracheal smooth muscel cells (HTSMCs). To test this hypothesis, this proposal will investigate the molecular mechanisms of ROS associated with COX-2 expression in response to cigarette smoke in HTSMCs. These results will provide new insights into the mechanisms of cigarette smoke action, supporting the hypothesis that cigarette smoke may contribute to promote inflammatory responses involved in the development of airway diseases. Increased understanding of signal transduction mechanisms underlying COX-2 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies. These experiments should provide new insights into the mechanisms involved in airway inflammation and lung degeneration.

Project ID:PC10001-0204
External Project ID:NSC98-2314-B182A-095-MY3