Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass

Background-Acute lung injury (ALI) after cardiopulmonary bypass (CPB) resul ts from sequential priming and activation of neutrophils. Activated neutrop hils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membr anes and the extracellular matrix, resulting in an ALI clinically defined a s adult respiratory distress syndrome (ARDS). We hypothesized that treatmen t with a potent MMP and elastase inhibitor, a chemically modified tetracycl ine (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB. Methods and Results-Anesthetized Yorkshire pigs were randomized to 1 of 5 g roups: control (n=3); CPB (n=5), femoral-femoral hypothermic bypass for 1 h our; LPS (n=7), sham bypass followed by infusion of low-dose Escherichia co li lipopolysaccharide (LPS; 1 mu g/kg); CPB + LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults plus intravenous CMT-3 dosed to obtain a 25-mu mol/L blood concentration. CPB+LPS caused severe lung injury, as demo nstrated by a significant fall in PaO2 and an increase in intrapulmonary sh unt compared with all groups (P<0.05). These changes were associated with s ignificant pulmonary infiltration of neutrophils and an increase in elastas e and MMP-9 activity. Conclusions-All pathological changes typical of ALI after CPB were prevente d by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effecters.