Alveolar epithelial injury is a major factor in the mechanism of Acute Respiratory Distress Syndrome (ARDS). Repair of the epithelial barrier is crucial for the restoration of normal lung function but the molecular mechanisms regulating repair are not well understood. Our objective is to define the role of alveolar type II cells during alveolar repair by using novel molecular approaches that include genetically-modified mouse models.
The normal alveolar epithelium is composed of two types of cells: flat type I cells, which comprise 95% of the gas-exchange surface, and cuboidal type II cells that secrete pulmonary surfactant. Injury of alveoli activates programs in potent type II cells that result in proliferation and trans-differentiate into type I cells leading to alveolar barrier repair. Thus, type II cells function as “facultative progenitor cells” that have a crucial role in repair of the alveolar surface. We utilized a mouse model of Pseudomonas aeruginosa (PA) infection-induced lung injury and discovered that a sub-fraction of type II cells were activated during alveolar injury to express fork-head transcription factor (FoxM1). In addition, using a type II cell specific FoxM1 knock-out mouse model, we have identified a critical role for FoxM1 in mediating the transition of type II cells to type I cells required for the recovery from PA induced injury. We are currently focusing on two areas: 1) To determine the factors that induce the progenitor cells phenotype of type II cell. 2) To determine the consequences of functionally disrupting activated type II cells in the mechanism of lung fibrosis.