Matrix Metalloproteinase Inhibitor Prevents Acute Lung Injury After Cardiopulmonary Bypass

Abstract

Background-Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (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 groups: control (nϭ3); CPB (nϭ5), femoral-femoral hypothermic bypass for 1 hour; LPS (nϭ7), sham bypass followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1 g/kg); CPBϩLPS (nϭ6), both insults; and CPBϩLPSϩCMT-3 (nϭ5), both insults plus intravenous CMT-3 dosed to obtain a 25-mol/L blood concentration. CPBϩLPS caused severe lung injury, as demonstrated by a significant fall in PaO 2 and an increase in intrapulmonary shunt compared with all groups (PϽ0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity. Conclusions-All pathological changes typical of ALI after CPB were prevented 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 effectors. (Circulation. 1999;100:400-406.)

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.…”

“…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.…”

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

“…Animals receiving CPB and LPS developed ARDS-like pathology with 60% survival. Clinical features of ARDS were prevented by CMT-3 treatment, with a 100% survival rate compared with 60% during the 270 min of experimentation [41]. It is also worth noting that all these animals were subject to tidal volumes of 12 mL?kg -1 during this experiment, which essentially provides another injurious stimulus to the lungs in all groups.…”

“…In a CPB pig model of lung injury, CMT-3 was used to assess the response to MMP inhibition [41]. 30 min after CPB was initiated, either low-dose LPS (1 mg?kg -1 ), a control or simultaneous LPS and CMT-3 were given.…”

Targeting the Proteolytic Arsenal of Neutrophils

“…In this issue of Circulation, Carney et al 18 have tested the hypothesis that increased metalloproteinase and elastase levels play a pathophysiological role in pulmonary microvascular injury in a porcine model of postpump syndrome. The authors used CPB plus endotoxin challenge to induce postpump-like syndrome on the basis of their previous experience showing that both a priming stimulus (CPB) and a secondary trigger (endotoxin) are necessary to create the syndrome in this model.…”