Pulmonary fibrosis is a final common pathway in many forms of interstitial lung diseases (ILD). Currently there are no effective treatments for most fibrotic lung diseases, and the development of preventative and therapeutic strategies remains limited by incomplete understanding of the cellular and molecular mechanisms underlying alveolar fibrosis. Monogenic disorders provide a unique opportunity to study lung fibrogenesis from the vantage point of a primary molecular defect. Hermansky-Pudlak Syndrome (HPS) is a family of autosomal recessive disorders involving dysfunction of intracellular trafficking and abnormal lysosome-related organelle biogenesis. Pulmonary fibrosis is highly penetrant in HPS types 1, 2, and 4, but does not occur in other HPS subtypes. In HPS patients with fibrotic predisposition, alveolar epithelial type II cells are hyperplastic with irreular lamellar bodies and lipid accumulation. In addition, macrophage-mediated inflammation precedes pulmonary fibrosis in HPS patients. We have shown that naturally-occurring HPS mice reliably model important features of the human disease, including HPS genotype-specific alveolar macrophage (AM) activation and susceptibility to pro-fibrotic stimuli. In addition, we have recently demonstrated that the alveolar epithelium is the primary driver of fibrotic susceptibility, as transgenic epithelial-specific correction of the HPS2 defect significantly attenuated type II cell apoptosis, excess monocyte-chemotactic protein-1 (MCP-1) secretion, AM activation, and susceptibility to bleomycin-induced fibrosis. Although the mechanisms by which HPS trafficking defects regulate type II cell phenotype remain poorly defined, our preliminary data demonstrate excess oxidative stress in type II cells of HPS2 mutant mice, as well as markedly increased expression of Nox4. Based on these data, we propose the hypothesis that HPS trafficking defects result in increased Nox4- dependent reactive oxygen species (ROS) production and enhanced secretion of mediators, including MCP-1, that recruit and activate AMs in the local microenvironment. After exposure to injurious stimuli, marginally compensated type II cells are at increased risk for apoptosis, which accelerates the fibrotic response in conjunction with activated AMs. To test this hypothesis, we propose the following specific aims using HPS models which experimentally mimic human disease: 1) to define the role of oxidative stress in HPS type II cell dysfunction, 2) to investigate the mechanisms underlying susceptibility to bleomycin-induced type II cell apoptosis and accelerated fibrosis in HPS mice, and 3) to determine the epithelial-derived factors regulating AM activation in HPS and the role of activated AMs in HPS-related pulmonary fibrosis. Overall, our studies will lead to improved understanding of the mechanisms of type II cell dysfunction in HPS and could facilitate therapeutic strategies for this fatal disorder. Because type II cell dysfunction is a unifying feature of many fibrotic lung diseases, further study of HPS trafficking defects will likey elucidate mechanisms of pulmonary fibrosis with broad relevance.

Public Health Relevance

Interstitial lung diseases (ILD) are disorders that cause shortness of breath and respiratory compromise due to progressive pulmonary fibrosis. Hermansky-Pudlak Syndrome (HPS) is an inherited disorder in which almost all affected adults develop fatal pulmonary fibrosis. This proposal will use HPS mouse models and other powerful genetic mouse models to understand what causes pulmonary fibrosis in HPS and how new therapies might be developed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Eu, Jerry Pc
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Vanderbilt University Medical Center
Schools of Medicine
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