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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
6R01HL119503-04
Application #
9066214
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Reineck, Lora A
Project Start
2013-08-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Burman, Ankita; Kropski, Jonathan A; Calvi, Carla L et al. (2018) Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein. JCI Insight 3:
Kook, Seunghyi; Qi, Aidong; Wang, Ping et al. (2018) Gene-edited MLE-15 Cells as a Model for the Hermansky-Pudlak Syndromes. Am J Respir Cell Mol Biol 58:566-574
Sucre, Jennifer M S; Deutsch, Gail H; Jetter, Christopher S et al. (2018) A Shared Pattern of ?-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis. Am J Pathol 188:853-862
Kropski, Jonathan A; Young, Lisa R; Cogan, Joy D et al. (2017) Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 195:1423-1428
O'Brien, Kevin J; Lozier, Jay; Cullinane, Andrew R et al. (2016) Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism. Mol Genet Metab 119:284-287
Benjamin, John T; van der Meer, Riet; Im, Amanda M et al. (2016) Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development. Am J Pathol 186:1786-1800
Deutsch, Gail H; Young, Lisa R (2016) Lipofibroblast Phenotype in Pulmonary Interstitial Glycogenosis. Am J Respir Crit Care Med 193:694-6
Saxon, Jamie A; Sherrill, Taylor P; Polosukhin, Vasiliy V et al. (2016) Epithelial NF-?B signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment. Oncoimmunology 5:e1168549
Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304
Young, Lisa R; Gulleman, Peter M; Short, Chelsi W et al. (2016) Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. JCI Insight 1:e88947

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