Airway epithelia are major targets of environmental toxicants. Airway injury due to inhalation of deleterious environmental agents contributes to the etiology of many pulmonary diseases including asthma, cystic fibrosis, acute lung injury, and acute respiratory distress syndrome. Normally following injury, airway epithelia rapidly undergo a series of progressive and cumulative changes to repair the wounded area. First, a provisional matrix mostly derived from fibrin and fibronectin accumulates at the denuded region. Second, airway epithelial cells at the margins of the injured area dedifferentiate and detach from their neighboring cells and migrate across the matrix to restore epithelial integrity. Third, the newly arrived cells proliferate to fill the injured area resulting in a dedifferentiated epithelium. Finally, the cells loose their proliferative capacity, reestablish contacts with neighboring cells, and redifferentiate to restore normal epithelial architecture and barrier function. Although this process has been well-characterized in a variety of different experimental and clinical settings, the exact cellular and molecular mechanisms mediating the repair process remain to be elucidated. Recently, our laboratory developed an in vitro system to study airway repair. Using this system, we made the interesting observation that expression of the MUC1 epithelial membrane protein was initially down-regulated followed by an abrupt and dramatic up-regulation during repair. Based upon these observations, we hypothesize that some of the steps of post-injury repair are mediated by transient alteration of MUC1 expression. In particular, through its interactions with other cellular proteins (beta-catenin, ICAM-1), we suggest that decreased MUC1 expression at an early stage of repair is responsible for cell detachment and proliferation while increased MUC1 at later stages of repair mediates the opposite effects. Successful completion of this study will lay the foundation for our future projects to identify the role of MUC1 in repair using in vivo animal models and clinical samples from patients with environmentally-injured airways. We expect that future therapies for respiratory diseases, particularly those related to toxicant inhalation, will be developed based upon clinical modulation of MUC1 expression. ? ?
