Tobacco smoke (TS) exposure damages to lung epithelium and leads to chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States. Our findings and those of others suggest that environmental, passive TS exposure induced lung injury involves programmed alveolar epithelial cell death and abnormal fibrin turnover. In this project, we will determine how p53, a protein causing epithelial cell death, regulates plasminogen activator inhibitor-1 (PAI-1), an inhibitor of the blood clot dissolution system, to influence the viability of the lung epithelium. Increased alveolar expression of PAI-1 results in locally suppressed fibrinolysis and promotes the extensive fibrin deposition that characterizes virtually all forms of lung injuries, including those caused by environmental TS exposure. Alveolar type II epithelial cell (ATII cell) apoptosis, mediated by the tumor suppressor protein, p53, is likewise independently linked to the pathogenesis of TS-induced lung injuries such as COPD. ATII cells are a major source of PAI-1 in the lungs and also express p53. We recently presented evidence indicating that induction of p53 in injured ATII cells up-regulates both PAI-1 mRNA and protein expression. Our recent studies indicated that exposure to environmental or passive TS is linked to a disproportionate increase in p53 and PAI-1 expression and that inhibition of either p53 or PAI-1 in ATII cells mitigates apoptosis. ATII cells of mice lacking either p53 or PAI-1 expression do not undergo TS exposure-induced apoptosis, whereas ATII cells from wild-type mice show increased p53 and PAI-1 expression and apoptosis. How these newly recognized interactions contribute to the pathogenesis of TS-induced lung injury is unclear. Our project addresses this critical gap. We will use a range of molecular and novel interventional approaches that include the use of knockout mice to address our working hypothesis, which is that p53-mediated increase in expression of PAI-1 promotes ATII cell apoptosis. This is central to the pathogenesis of TS-induced lung injury and can be reversed by caveolin-1 scaffolding peptide (CSP), offering a novel interventional approach for this form of lung injury. Our objective is to determine how CSP improves TS-induced lung injury by targeting p53-mediated PAI-1 expression and ATII cell apoptosis.
Our Specific Aims are: 1) to elucidate the mechanism by which CSP modulates p53-induced PAI-1 expression and ATII cell apoptosis during TS-induced lung injury. 2) to determine how reversal of TS-induced changes in the expression of microRNA-34a and surfactant protein-C by CSP mitigates ATII cell apoptosis and lung injury. We will illuminate how p53-induced PAI-1 affects alveolar injury caused by TS exposure using murine WT, p53-/- and PAI-1-/- models. This project will advance the field by elucidating how p53-mediated induction of PAI-1 regulates ATII cell viability and modulates the outcome of lung injury. The proposed interventional studies may also define new, pharmacologically targeted approaches to improve clinical outcomes for patients with lung injuries due to environmental TS exposure.
Exposure to tobacco smoke (TS) damages the lung lining (lung epithelium) and can lead to chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. Our findings and the literature suggest that TS-induced lung injury involves alveolar epithelial cell death and abnormal fibrin turnover. In this project, e will determine how p53, a protein causing epithelial cell death, regulates PAI-1, an inhibitor of the blood clot dissolution system, to influence the viability of the lung epithelium
