Tobacco use and prevalence of chronic obstructive pulmonary disease (COPD) are significantly higher among veterans than non-veteran population. Airway and pulmonary vascular remodeling is the most critical process in the pathogenesis of COPD. Large amounts of reactive oxygen species (ROS) are released from activated inflammatory cells and other lung cells in COPD or from tobacco smoke (TS) per se. ROS are implicated in the development of airway and pulmonary vascular remodeling. However, little has been known about how ROS and TS lead to these pathological alterations. We have found that ROS and TS activates calpain in bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs) and that calpain mediates cell proliferation and collagen-I synthesis in PASMCs. Calpain is a family of calcium-dependent non- lysosomal neutral cysteine endopeptidases that act via limited proteolysis of substrate proteins in mammalian cells, including BSMCs and PASMCs. We have recently reported for the first time that global inhibition of calpain prevents pulmonary vascular remodeling induced by chronic hypoxia and monocrotaline. In preliminary experiments, we found that the specific calpain inhibitor, MDL28170, prevented ROS-induced increases in cell proliferation and protein levels of collagen-I in BSMCs and PASMCs. Transforming growth factor (TGF)/Smad pathway have been shown to play important roles in airway and pulmonary vascular remodeling. We have reported that calpain activates TGF1 by cleaving latent TGF1. This proposal is to study a novel hypothesis that calpain mediates ROS- and TS-induced cell proliferation and collagen synthesis in airway and pulmonary vascular smooth muscle cells via activation of intracellular TGF1 in TS-induced COPD. The protein and activity of calpain, cell proliferation and collagen synthesis will be determined in BSMCs and PASMCs with or without treatment of H2O2 and TS. Calpain activity will be manipulated using specific inhibitor, siRNA and over-expression of calpastatin genes. A novel intracrine TGF1 pathway will be studied in H2O2- and TS-treated cells. Moreover, the role of calpain in airway and pulmonary vascular remodeling will be evaluated in a COPD animal model using innovative inducible global and smooth muscle-specific calpain knockout mouse line. Finally, calpain will be pharmacologically targeted using a specific calpain inhibitor MDL28170 in a TS-induced COPD rat model. This proposal is novel because it will identify calpain as a mediator in airway and pulmonary vascular remodeling and calpain serves this role by activating intracellular TGF1 in BSMCs and PASMCs. A better understanding of the mechanistic insight will provide a strong rationale for manipulating calpain activities in the treatment of lung diseases such as COPD, pulmonary hypertension and cor pulmonale. Completion of this project will help find novel treatments for COPD and in turn improve the life and care of veterans.

Public Health Relevance

Tobacco use and prevalence of chronic obstructive pulmonary disease (COPD) are significantly higher among veterans than non-veteran population. Tobacco smoke is the primary risk factor for COPD and is estimated to be responsible for at least 75% of COPD deaths. Tobacco smoke-induced COPD is one of the major causes of morbidity among veterans in terms of both healthcare cost and suffering. Thus, it is very important to understand the mechanism of tobacco smoke-induced lung diseases. This proposal will determine the mechanism of airway and pulmonary vascular remodeling in tobacco smoke- induced COPD. Completion of this project will help find novel treatments for COPD and in turn improve the life and care of veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002035-04
Application #
9487112
Study Section
Respiration (PULM)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Charlie Norwood VA Medical Center
Department
Type
DUNS #
010116408
City
Augusta
State
GA
Country
United States
Zip Code
30904
Cai, Pengcheng; Kovacs, Laszlo; Dong, Sam et al. (2017) BMP4 inhibits PDGF-induced proliferation and collagen synthesis via PKA-mediated inhibition of calpain-2 in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 312:L638-L648
Hao, Jielu; Wei, Qingqing; Mei, Shuqin et al. (2017) Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6. Kidney Int 91:106-118
Yang, Pu; Hong, Michael S; Fu, Chunhua et al. (2016) Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions. Surgery 159:602-12
Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan et al. (2016) Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 54:384-93
Kondrikov, Dmitry; Fulton, David; Dong, Zheng et al. (2015) Heat Shock Protein 70 Prevents Hyperoxia-Induced Disruption of Lung Endothelial Barrier via Caspase-Dependent and AIF-Dependent Pathways. PLoS One 10:e0129343
Chen, Li-Jun; Ye, Hong; Zhang, Qian et al. (2015) Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells. Toxicol Appl Pharmacol 283:75-82
Abeyrathna, Prasanna; Su, Yunchao (2015) The critical role of Akt in cardiovascular function. Vascul Pharmacol 74:38-48
Lu, Ankang; Zuo, Caojian; He, Yuhu et al. (2015) EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-?1 signaling. J Clin Invest 125:1228-42
Li, Feng-Zhi; Cai, Peng-Cheng; Song, Lin-Jie et al. (2015) Crosstalk between calpain activation and TGF-?1 augments collagen-I synthesis in pulmonary fibrosis. Biochim Biophys Acta 1852:1796-804
Wang, Shixuan; Livingston, Man J; Su, Yunchao et al. (2015) Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways. Autophagy 11:607-16

Showing the most recent 10 out of 11 publications