Reactive Oxygen Species-Dependent Calpain Activation Contributes to Airway and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Jing Zhu, Laszlo Kovacs, Weihong Han, Guojun Liu, Yuqing Huo, Rudolf Lucas, David Fulton, Peter A. Greer, Yunchao Su

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Aims: Airway and pulmonary vascular remodeling is an important pathological feature in the pathogenesis of chronic obstructive pulmonary disease (COPD). Tobacco smoke (TS) induces the production of large amounts of reactive oxygen species (ROS) in COPD lungs. We investigated how ROS lead to airway and pulmonary vascular remodeling in COPD. Results: We used in vitro bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs), in vivo TS-induced COPD rodent models, and lung tissues of COPD patients. We found that H2O2 and TS extract (TSE) induced calpain activation in BSMCs and PASMCs. Calpain activation was elevated in smooth muscle of bronchi and pulmonary arterioles in COPD patients and TS-induced COPD rodent models. Calpain inhibition attenuated H2O2-and TSE-induced collagen synthesis and proliferation of BSMCs and PASMCs. Exposure to TS causes increases in airway resistance, right ventricular systolic pressure (RVSP), and thickening of bronchi and pulmonary arteries. Calpain inhibition by smooth muscle-specific knockout of calpain and the calpain inhibitor MDL28170 attenuated increases in airway resistance, RVSP, and thickening of bronchi and pulmonary arteries. Moreover, smooth muscle-specific knockout of calpain did not reduce TS-induced emphysema in the mouse model, but MDL28170 did reduce TS-induced emphysema in the rat model. Innovation: This study provides the first evidence that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling in TS-induced COPD. Calpain might be a novel therapeutic target for the treatment of COPD. Conclusion: These results indicate that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling and pulmonary hypertension in COPD.

Original languageEnglish (US)
Pages (from-to)804-818
Number of pages15
JournalAntioxidants and Redox Signaling
Volume31
Issue number12
DOIs
StatePublished - Oct 20 2019

Keywords

  • COPD
  • calpain
  • reactive oxygen species
  • tobacco smoke

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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