Effects of matrix metalloproteinase inhibitor on ventilator-induced lung injury in rats

Background: Many inflammatory mediators and collagenases are involved in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The increase of matrix metalloproteinase-9 (MMP-9, gelatinase-B) produced mainly by inflammatory cells was reported in many ALI models and ARDS patients. Cyclic mechanical stress also can induce MMP-9 production from alveolar macrophages and connective tissue cells. In this study, the expression of MMP-9 in ventilator-induced lung injury (VILI) model and the effects of matrix metalloproteinase inhibitor (MMPI) on VILI were investigated. Methods: Eighteen Sprague-Dawley rats were divided into three groups: low tidal volume (LVT, 7mL/Kg tidal volume, 3 cmH₂O PEEP, 40/min.), high tidal volume (HVT, 30mL/Kg tidal volume, no PEEP, 40/min) and high tidal volume with MMPI (HVT+MMPI) groups. Mechanical ventilation was performed in room air for 2 hours. The 20 mg/Kg of CMT-3 (chemically modified tetracycline-3, 6-demethyl 6-deoxy 4-dedimethylamino tetracycline) was gavaged as MMPI from three days before mechanical ventilation. The degree of lung injury was measured with wet-to-dry weight ratio and acute lung injury score. Expression of MMP-9 was studied by immunohistochemical stain with a mouse monoclonal anti-rat MMP-9 IgG₁. Results: In the LVT, HVT and HVT+MMPI groups, the wet-to-dry weight ratio was 4.70±0.14, 6.82±1.28 and 4.92±0.98, respectively. In the HVT group, the ratio was significantly higher than other groups (p<0.05). Acute lung injury score measured by five-point scale was 3.25±1.17, 12.83±1.17 and 4.67±0.52, respectively. The HVT group was significantly damaged by VILI and MMPI protects injuries by mechanical ventilation (p<0.05). Expression of MMP-9 measured by four-point scale was 3.33±2.07, 12.17±2.79 and 3.60±1.95, respectively, which were significantly higher in the HVT group (p<0.05). Conclusion: VILI increases significantly the expression of MMP-9 and MMPI prevents lung injury induced by mechanical ventilation through the inhibition of MMP-9.