Although the etiology of idiopathic pulmonary fibrosis (IPF) remains poorly defined, several lines of evidence suggest that alveolar epithelial cells (AECs) play key roles in disease pathogenesis. We have identified mutations in the gene encoding surfactant protein C (SP-C) that affect AEC function in some patients with the familial form of IPF, familial interstitial pneumonia (FIP). Data presented in this application indicate that abnormal processing of pro-SP-C by AECs leads to endoplasmic reticulum (ER) stress, activation of the unfolded protein response, and cell death. In addition, our data show that ER stress occurs frequently in AECs in late stage IPF (and FIP), suggesting that this pathway commonly contributes to disease progression. Other preliminary data show that herpesviruses, which are commonly identified in IPF, are localized to AECs and could contribute to ER stress and AEC injury. Further, we have identified loss-of-function mutations in genes for essential components of telomerase that segregate with disease in some FIP families. In the lungs, it is possible that defective telomerase leads to telomere shortening followed by cell cycle arrest and apoptosis of type II AECs. Since most patients have advanced disease at the time of diagnosis, it has not been possible to define early events in IPF pathogenesis and controversy continues about whether mediators and pathways implicated in fibrotic remodeling represent primary disease mechanisms or occur as a result of an ongoing injury-repair process. These issues are particularly relevant to the study of AECs, which become hyperplastic in areas of fibrotic remodeling. Identification of patients with early FIP provides a valuable resource for investigations aimed at defining primary disease mechanisms. We have currently identified 61 asymptomatic individuals with radiographic changes consistent with early FIP by screening 417 at risk individuals. This group and additional subjects with early FIP identified by screening with high resolution computed tomography scanning will undergo bronchoscopy for sample collection to test the following hypothesis. Genetic or acquired factors that increase the susceptibility of lung epithelial cells to apoptosis underlie the pathogenesis of familial and sporadic forms of IPF. Exposure of vulnerable epithelial cells to common injurious/toxic environmental stimuli results in extensive injury with limited capacity for alveolar repair, leading to fibrotic remodeling. Identification of common phenotypic manifestations of vulnerable epithelial cells, such as ER stress or telomere shortening, will better define disease pathogenesis and identify novel targets for future therapeutic interventions. The following specific aims will investigate the role of alveolar epithelium in early FIP: 1) to evaluate epithelial cell injury/apoptosis, markers of ER stress, and surfactant protein production in the lungs of patients with early FIP, 2) to investigate whether herpesvirus infection occurs in early FIP, contributes to ER stress, and is associated with alveolar epithelial cell injury and, 3) to determine whether differential telomere length occurs in epithelial cells from patients with early FIP and correlates with epithelial cell injury. PROJECT NARRATIVE: Diseases that result in progressive fibrosis of the lung, including idiopathic pulmonary fibrosis (IPF), are a substantial cause of morbidity and mortality for which there are no effective treatments. We have identified a unique cohort of individuals with the earliest form of pulmonary fibrosis that will be studied in order to determine factors that are essential for disease initiation and early progression. By elucidating the critical components of early stage disease, our study will define novel targets for future therapeutic interventions.
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