MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema
Journal
American Journal of Physiology - Lung Cellular and Molecular Physiology
Journal Volume
315
Journal Issue
3
Pages
L432-L442
Date Issued
2018
Author(s)
Abstract
Because of the expansion of aging and smoking populations, chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide in 2030. Therefore, it is pertinent to develop effective therapy to improve management for COPD. Cigarette smoke-medi-ated protease-antiprotease imbalance is a major pathogenic mechanism for COPD and results in massive pulmonary infiltration of neutrophils and macrophages, releasing excessive neutrophil elastase (NE) and matrix metalloproteinases (MMPs). Our previous studies indicated that placenta growth factor (PGF) and PGF-triggered downstream signaling molecules mediate NE-induced lung epithelial cell apoptosis, which is a major pathogenic mechanism for pulmonary emphysema. However, the relationship between MMP-directed COPD and PGF remains elusive. We hypothesize that MMPs may upregulate PGF expression and be involved in MMP-mediated pathogenesis of COPD. In this study, we demonstrate that only MMP-12 can increase the expression of PGF by increasing early-growth response protein 1 (Egr-1) level through the activation of protease-activated receptor 1 (PAR-1). The PGF-mediated downstream signaling molecules drive caspase-3 and caspase-9-dependent apoptosis in bronchial epithelial cells. Both the upregulation of PGF by MMP-12 and PGF downstream signaling molecules with pulmonary apoptosis and emphysema were also demonstrated in animals. Given these findings, we suggest that both human COPD-associated elastases, NE, and MMP-12, upregulate PGF expression and promote the progression of emphysema and COPD. ? 2018 American Physiological Society. All rights reserved.
SDGs
Other Subjects
caspase 3; caspase 9; cigarette smoke; early growth response factor 1; leukocyte elastase; macrophage elastase; matrix metalloproteinase; placental growth factor; proteinase; proteinase activated receptor 1; proteinase inhibitor; Casp3 protein, mouse; Casp9 protein, mouse; caspase 3; caspase 9; early growth response factor 1; Egr1 protein, mouse; macrophage elastase; matrix metallopeptidase 12, mouse; placental growth factor; proteinase activated receptor 1; animal experiment; animal model; animal tissue; apoptosis; Article; bronchus; chronic obstructive lung disease; controlled study; epithelium cell; human; human cell; immunohistochemistry; lung emphysema; lung infiltrate; macrophage; male; mouse; neutrophil; nonhuman; pathogenesis; priority journal; protein expression; signal transduction; upregulation; animal; biosynthesis; chronic obstructive lung disease; genetics; knockout mouse; lung edema; metabolism; pathology; upregulation; Animals; Caspase 3; Caspase 9; Early Growth Response Protein 1; Humans; Matrix Metalloproteinase 12; Mice; Mice, Knockout; Placenta Growth Factor; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Receptor, PAR-1; Signal Transduction; Up-Regulation
Publisher
American Physiological Society
Type
journal article