Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury

Abstract

Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: 1) low tidal volume (LVT), 7 ml/kg of tidal volume (VT); 2) high tidal volume (HVT), 30 ml/kg of VT; and 3) HVT with MMP inhibitor (HVT+MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT+MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT+MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…During VILI, high airway pressures and volumes lead to cell stretch, causing epithelial damage and an inflammatory response within the lungs. Increased levels of MMPs have been documented in different models of acute lung injury (8,13,27) and in the special case of VILI (14,25). MMP-9 is one of the most studied MMPs.…”

“…Currently, MMPs are viewed as modulators of cell-cell and cell-matrix interactions (37). Among them, MMP-9 (gelatinase B) has gained some attention in different models of lung injury (39,42) including VILI (14,25). The levels of MMP-9 have also been found to be raised in patients with acute lung injury (13,40,50).…”

“…On the basis of these findings, it has been suggested that MMP-9 inhibition could be useful in models of sepsis (42), acute lung injury (8), and VILI (14,25) by decreasing the inflammatory response and tissue damage. However, nonselective inhibitors can modify the activity of other enzymes, precluding any firm conclusion on the specific role of MMP-9.…”

Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro

“…Both of these are potent effectors of neutrophil-mediated inflammation and tissue damage. 15,16 We cannot, however, exclude the possibility that at longer exposure times, in excess of 10 minutes, significant Ca 2+ influx and cytotoxicity may occur.…”

Neutrophil elastase ameliorates matrix metalloproteinase-9 to promote lipopolysaccharide-induced acute lung injury in mice 1

“…In COPD, NE is known to activate MMPs, including MMP-9. However, the exact role of NE in ALI and ARDS is unclear 10,11 .…”