Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes, particularly HPS-1. In at-risk HPS genotypes, pulmonary fibrosis has been reported to develop in all patients typically in the third to fourth decades of life, with patients succumbing within 3 to 10 years of diagnosis in the absence of lung transplantation. Despite knowledge of the underlying genetic defects, there are currently no therapeutic or preventative approaches for HPS pulmonary fibrosis, or for most fibrotic lung diseases. HPS pulmonary fibrosis exhibits some clinical and radiographic features found in Idiopathic Pulmonary Fibrosis (IPF), but occurs at a younger age. Lung histology from affected HPS patients also shares some similarities to the patterns observed in IPF, including hyperplastic type II alveolar epithelial cells (AECs). However, other features of HPS pulmonary fibrosis are not typical for IPF, including the presence of irregular lamellar bodies and lipid accumulation in AECs, and the presence of alveolar inflammation and alveolar macrophage activation. With a multitude of ongoing and planned treatment trials for IPF, it is essential to better understand the pathogenesis of HPS pulmonary fibrosis so that drugs proven to be effective in IPF can be considered for future studies in HPS patients. Our preliminary data demonstrate increased oxidative stress in the lungs of HPS mouse models and in lung tissue from HPS patients. Our hypothesis is that HPS trafficking mutations result in oxidative stress, which renders already vulnerable AECs susceptible to environmental 'second hits'over time that result in pulmonary fibrosis. To test this hypothesis and prepare for clinical trials in HPS, we propose the following specific aims: 1) To identify the earliest measurable pulmonary disease activity in individuals at-risk for HPS pulmonary fibrosis, 2) To determine whether HPS patients exhibit increased markers of oxidative stress, and whether oxidative stress measures correlate with pulmonary disease activity and/or pulmonary disease risk in patients with HPS, and 3) To determine whether molecular signatures of HPS pulmonary fibrosis are similar to that observed in other causes of pulmonary fibrosis. Overall, these studies will provide insights into the pathogenesis of HPS pulmonary fibrosis and prepare for clinical trials. Identification of biologic outcome measures will aid in future clinical trials in this rare disease.

Public Health Relevance

Hermansky-Pudlak Syndrome is associated with highly penetrant and fatal pulmonary fibrosis in some subtypes, and no therapies other than lung transplantation are available. These studies will prepare for clinical trials in HPS by establishing an early disease cohort of HPS patients who are 'trial-ready.'In addition these studies will facilitate development of predictive biomarkers, provide insights into disease pathogenesis and identify potential therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Eu, Jerry Pc
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Cincinnati Children's Hospital Medical Center
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