Recent evidence points to a critical role for lung epithelial cells in determining the extent and progression of lung fibrosis. The importance of epithelial cells in fibrogenesis is highlighted by the identification of mutations in the epithelia-restricted genes, surfactant protein C (SFTPC) and SFTPA2, that are associated with familial IPF. Mutant forms of SFTPC impact protein folding in the endoplasmic reticulum (ER), resulting in ER stress. During this funding period, we found that ER stress is common in patients with sporadic and familial IPF and that markers of ER stress localize to epithelial cells in areas of lung parenchymal remodeling. We generated a transgenic mouse model in which expression of L188Q SFTPC is localized to type II alveolar epithelial cells (AECs). Transgene induction in this model leads to ER stress, but is not sufficient to cause fibrosis. However, treating these mice with low dose bleomycin results in a marked exacerbation of lung fibrosis as well as increased apoptosis of AECs and increased accumulation of fibroblasts, including fibroblasts derived via epithelial-mesenchymal transition (EMT). Our studies support the concept that ER stress in AECs makes these cells vulnerable to fibrotic stimuli, but a 'second hit'is necessary for development of lung fibrosis. In order to begin to identify relevant stimuli (i.e. - second hits) tat lead to progressive fibrosis in the setting of 'vulnerable'epithelial cells, we infected L188Q SFTPC expressing mice with the murine gamma herpesvirus (MHV68) and found that MVH68 infection in L188Q SFTPC expressing mice (but not wild type mice) results in progressive fibrosis. In addition, we recently showed that induction of ER stress in AECs in vitro results in EMT via endogenous activation of Src and Smad2/3 pathways. Based on preliminary data, we propose the hypothesis that ER stress in lung epithelial cells contributes to fibrotic remodeling by altering susceptibility to environmental stimuli (including herpesviruses and cigarette smoke). Depending on the severity and timing of the insult, ER stress predisposes epithelial cells to apoptosis, EMT, or a pro-fibrotic epithelial phenotype through alterations in intracellular signaling pathways, including Smad2/3 and Src. Interventions to reduce or modify the ER stress response will be effective in limiting progressive lung fibrosis.
Specific aims will: 1) define the mechanisms by which herpesvirus infection causes lung fibrosis in mice with inducible expression of mutant surfactant protein C in type II AECs, 2) investigate ER stress dependent pathways in type II AECs that mediate profibrotic phenotypes, and 3) test the impact of cigarette smoke on development of lung fibrosis in the setting of underlying ER stress and investigate whether ER stress reducing agents can block fibrotic remodeling. Together, these studies will advance the study of lung fibrosis by developing more relevant mouse models to study lung fibrosis, defining the vulnerable state of AECs that facilitates lung fibrosis, and identifying novl therapeutic approaches to ameliorate lung fibrosis based on improved ER function.

Public Health Relevance

Progressive fibrotic lung diseases frequently lead to respiratory failure and death. Studies in this proposal are based on the idea that altered protein processing in the endoplasmic reticulum produces a vulnerable state in the lungs that predisposes to fibrotic remodeling following exposure to noxious environmental stimuli. These studies will provide a better understanding of the basic mechanisms of disease pathogenesis and suggest new treatment approaches for progressive lung fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-G (02))
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Eu, Jerry Pc
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A et al. (2018) Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia. BMC Bioinformatics 19:18
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Hewlett, Justin C; Kropski, Jonathan A; Blackwell, Timothy S (2018) Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biol 71-72:112-127
Kropski, Jonathan A; Blackwell, Timothy S (2018) Endoplasmic reticulum stress in the pathogenesis of fibrotic disease. J Clin Invest 128:64-73
Lentz, Robert J; Taylor, Trevor M; Kropski, Jonathan A et al. (2018) Utility of Flexible Bronchoscopic Cryobiopsy for Diagnosis of Diffuse Parenchymal Lung Diseases. J Bronchology Interv Pulmonol 25:88-96
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Polosukhin, Vasiliy V; Richmond, Bradley W; Du, Rui-Hong et al. (2017) Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling. Am J Respir Crit Care Med 195:1010-1021
Kropski, Jonathan A; Reiss, Sara; Markin, Cheryl et al. (2017) Rare Genetic Variants in PARN Are Associated with Pulmonary Fibrosis in Families. Am J Respir Crit Care Med 196:1481-1484
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

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