MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema

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-mediated 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.

Impact of aging on inflammatory and immune responses during elastin peptide-induced murine emphysema

“…In contrast, aging alone, as evaluated in PBS-or VVGPGAtreated mice, does not influence the emphysema process. Contribution of macrophage-and neutrophil-derived proteases in initiating the emphysema process has been clearly described (6,22,42,43). Here we report that MMP-2, -9, and -12 are present in significant amounts in BALF during the initial (from day 3) and later (beyond day 14) phases of EP-induced pulmonary emphysema, and that these proteases are higher and earlier expressed in the BALF of elderly mice.…”

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

“…Whether these three MMPs cleave PAR2 is not clear, although PAR2 activation by trypsin induced secretion of MMP-9 in human airways, suggesting that MMP-9 is a PAR2-activating protease [93]. In mice, PAR1 expression was regulated by MMP-12, and activated PAR1 increased MMP-12 secretion [94, 95]. A similar feedback loop involving MMP-12 and PAR2 has been reported in mice [96].…”

TRPV4—A Missing Link Between Mechanosensation and Immunity

“…Conversely, activation of protease-activated receptor (PAR)-2 by thrombin suppresses TRPV4 activity in macrophages and resolves lung injury (74). Similarly, PARs are also activated by neutrophil elastase (NE), matrix metalloproteases (MMPs) or other microbial proteases (33,(75)(76)(77)(78)(79) which has been implicated to degrade ECM and thereby causing remodeling and matrix stiffening during infection (33,63,73,80).…”