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Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

Department of Medicine, Division of Pulmonary and Critical Care, University of Cincinnati; Department of Pediatrics, Division of Pulmonary Medicine, and Department of Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Francis X. McCormack, M.D., University of Cincinnati, Pulmonary, Critical Care, and Sleep Medicine, 231 Albert Sabin Way ML 0564, Cincinnati, OH 45267. E-mail: frank.mccormack{at}uc.edu

Pulmonary inflammation, abnormalities in type II cell and macrophage morphology, and pulmonary fibrosis are features of Hermansky-Pudlak Syndrome (HPS), a recessive disorder associated with intracellular trafficking defects. We have previously reported that "Pearl" (HPS2) and "Pale Ear" (HPS1) mouse models have pulmonary inflammatory dysregulation and constitutive alveolar macrophage (AM) activation (Young LR et al., J Immunol 2006;176:4361–4368). In the current study, we used these HPS models to investigate mechanisms of lung fibrosis. Unchallenged HPS1 and HPS2 mice have subtle airspace enlargement and foamy AMs, but little or no histologic evidence of lung fibrosis. Seven days after intratracheal bleomycin (0.025 units), HPS1 and HPS2 mice exhibited increased mortality and diffuse pulmonary fibrosis compared to strain-matched C57BL/6J wild-type (WT) mice. HPS mice had significantly increased collagen deposition, and reduced quasi-static and static compliance consistent with a restrictive defect. The early airway and parenchymal cellular inflammatory responses to bleomycin were similar in HPS2 and WT mice. Greater elevations in levels of TGF- and IL-12p40 were produced in the lungs and AMs from bleomycin-challenged HPS mice than in WT mice. TUNEL staining revealed apoptosis of type II cells as early as 5 h after low-dose bleomycin challenge in HPS mice, suggesting that type II cell susceptibility to apoptosis may play a role in the fibrotic response. We conclude that the trafficking abnormalities in HPS promote alveolar apoptosis and pulmonary fibrosis in response to bleomycin challenge.

Key Words: alveolar type II cells • alveolar macrophage • lung fibrosis • Hermansky-Pudlak • adaptor protein 3

CLINICAL RELEVANCE Hermansky-Pudlak Syndrome (HPS) is a highly penetrant genetic disorder of pulmonary fibrosis. This study demonstrates that bleomycin-challenged HPS mouse models have increased levels of TGF-, early type II cell apoptosis, and marked pulmonary fibrosis.