The goal of this proposal is to define the role that Bcl-2 expression (a gene that inhibits apoptosis or programmed cell death) plays in mucous cell metaplasia (MCM). MCM is the appearance of mucous secretory cells in regions of the respiratory tract normally devoid of these cells induced by exposure to bacterial endotoxins. Endotoxin exposure has been implicated in transient and chronic lung function impairment after exposure to organic dusts in cotton mills, poultry houses, swine confinement buildings, and saw mills. Pulmonary infections resulting from endotoxin-laden gram-negative bacteria are characterized by an influx of inflammatory cells and increased production and secretion of respiratory mucus. Both conditions are believed to be important factors in the pathogenesis of obstructive pulmonary disorders, such as asthma, chronic bronchitis and cystic fibrosis. The increased responsiveness of asthmatic individuals to endotoxin exposure may involve prolonged retention of the metaplastic mucous cells. Bcl-2 expression is found in metaplastic mucous cells induced by endotoxin exposure in rat pulmonary airways and in patients suffering from chronic obstructive pulmonary disease. Therefore, we will test the hypotheses that Bcl-2 plays a key role in prolonging the retention of metaplastic mucous cells in airway epithelia. An established rodent model of mucous cell metaplasia will be used (1) to determine which components of lavage fluid, harvested from endotoxin-instilled rats, enhance Bcl-2 expression and mucous cell metaplasia and (2) to define the role of Bcl-2 in the initiation and maintenance of mucous cell metaplasia by directly inhibiting Bcl-2 expression in endotoxin-induced MCM in vitro and in vivo using anti-sense oligonucleotides to Bcl-2. The modulation of Bcl-2 gene expression will help to clarify how endotoxin induces MCM and could form the basis for studies to identify other key factors in the apoptotic signaling pathway, including the surface receptors for the induction of Bcl-2. This information will contribute to the development of new gene-directed therapeutic strategies for controlling overproduction and hypersecretion of mucus in individuals with chronic respiratory diseases associated with mucous cell metaplasia.
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