Matrix Metalloproteinase-8 Inactivates Macrophage Inflammatory Protein-1α To Reduce Acute Lung Inflammation and Injury in Mice

Abstract

To determine the role of matrix metalloproteinase-8 (MMP-8) in acute lung injury (ALI), we delivered LPS or bleomycin by the intratracheal route to MMP-8−/− mice versus wild-type (WT) mice or subjected the mice to hyperoxia (95% O2) and measured lung inflammation and injury at intervals. MMP-8−/− mice with ALI had greater increases in lung polymorphonuclear neutrophils (PMNs) and macrophage counts, measures of alveolar capillary barrier injury, lung elastance, and mortality than WT mice with ALI. Bronchoalveolar lavage fluid (BALF) from LPS-treated MMP-8−/− mice had more MIP-1α than BALF from LPS-treated WT mice, but similar levels of other pro- and anti-inflammatory mediators. MIP-1α−/− mice with ALI had less acute lung inflammation and injury than WT mice with ALI, confirming that MIP-1α promotes acute lung inflammation and injury in mice. Genetically deleting MIP-1α in MMP-8−/− mice reduced the increased lung inflammation and injury and mortality in MMP-8−/− mice with ALI. Soluble MMP-8 cleaved and inactivated MIP-1α in vitro, but membrane-bound MMP-8 on activated PMNs had greater MIP-1α–degrading activity than soluble MMP-8. High levels of membrane-bound MMP-8 were detected on lung PMNs from LPS-treated WT mice, but soluble, active MMP-8 was not detected in BALF samples. Thus, MMP-8 has novel roles in restraining lung inflammation and in limiting alveolar capillary barrier injury during ALI in mice by inactivating MIP-1α. In addition, membrane-bound MMP-8 on activated lung PMNs is likely to be the key bioactive form of the enzyme that limits lung inflammation and alveolar capillary barrier injury during ALI.

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

“…It has a detrimental role in models of VILI [22] and lung fi brosis, due to IL-10 cleavage [23]. However, this enzyme may be benefi cial after lipopolysaccharide (LPS) or hyperoxia exposition [24]. Moreover, it may have a role in resolution stages of ALI, as it seems to be involved in neutrophil apoptosis through modulation of IL-4 levels [25].…”

A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization

“…These studies have demonstrated that the protective effect of MMP8 in these conditions is related to its influence on the behavior and function of neutrophils (14,16,21) or of eosinophils in the case of airway inflammation (16). The finding of the present study raises the possibility that the effect of MMP8 in some of these conditions might also be related to its role in M2-M polarization, which warrants further investigations.…”

“…Previous studies have shown that MMP8 has a protective effect against acute hepatitis (20), acute lung injury (14), airway inflammation (16), and cancers (21). These studies have demonstrated that the protective effect of MMP8 in these conditions is related to its influence on the behavior and function of neutrophils (14,16,21) or of eosinophils in the case of airway inflammation (16).…”

“…The best known substrates of MMP8 are types I, II, and III collagens. However, a growing number of other proteins have been reported to be also susceptible to cleavage by MMP8, including angiotensin-1 (10,11), chemokine (C-X-C motif) ligand 5 (CXCL5) (12), CXCL11 (13), and macrophage inflammatory protein-1 (14). Previously it was thought that only neutrophils produce MMP8, reflected by its alias names neutrophil collagenase and polymorphonuclear leukocyte collagenase.…”

“…Studies have shown that MMP8 can modulate the behavior and function of several cell types including neutrophils (14,15), eosinophils (16), smooth muscle cells (17), endothelial cells (18), and stem/progenitor cells (19), underlain by its proteolytic activity on matrix and non-matrix proteins. Furthermore, studies have shown that MMP8 is involved in a number of pathological conditions including atherosclerosis (11,19), acute hepatitis (20), acute lung injury (14), airway inflammation (16), and cancers (21). Because M play important roles in many pathological conditions, and given that M express MMP8, we investigated in this present study if MMP8 had a role in M differentiation and/or polarization.…”