Metalloproteinase inhibition prevents acute respiratory distress syndrome

Background. The acute respiratory distress syndrome (ARDS) occurs in patien ts with clearly identifiable risk factors, and its treatment remains merely supportive. We postulated that patients at risk for ARDS can be protected against lung injury by a prophylactic treatment strategy that targets neutr ophil-derived proteases. We hypothesized that a chemically modified tetracy cline 3 (COL-3), a potent inhibitor of neutrophil matrix metalloproteinases (MMPs) and neutrophil elastase (NE) with minimal toxicity, would prevent A RDS in our porcine endotoxin-induced ARDS model. Methods. Yorkshire pigs were anesthetized, intubated, surgically instrument ed for hemodynamic monitoring, and randomized into three groups: (1) contro l (n = 4), surgical instrumentation only; (2) lipopolysaccharide (LPS) (n = 4), infusion of Escherichia coli lipopolysaccharide at 100 mug/kg; and (3) COL-3 + LPS (n = 5), ingestion of COL-3 (100 mg/kg) 12 h before LPS infusi on. All animals were monitored for 6 h following LPS or sham LPS infusion. Serial bronchoalveolar lavage (BAL) samples were analyzed for MMP concentra tion by gelatin zymography. Lung tissue was fixed for morphometric assessme nt at necropsy. Results. LPS infusion was marked by significant (P < 0.05) physiological de terioration as compared with the control group, including increased plateau airway pressure (P-plat) (control = 15.7 +/- 0.4 mm Hg, LPS = 23.0 +/- 1.5 nim Hg) and a decrement in arterial oxygen partial pressure (PaO2) (LPS = 66 +/- 15 mm Hg, Control = 263 +/- 25 mm Hg) 6 h following LPS or sham LPS infusion, respectively. Pretreatment with COL-3 reduced the above pathophys iological changes 6 h following LPS infusion (P-plat = 18.5 +/- 1.7 rum Hg, PaO2 = 199 +/- 35 mm Hg; P = NS vs control). MMP-9 and MMP-2 concentration in BAL fluid was significantly increased between 2 and 4 h post-LPS infusi on; COL-3 reduced the increase in MMP-9 and MMP-2 concentration at all time periods. Morphometrically LPS caused a significant sequestration of neutro phils and monocytes into pulmonary tissue. Pretreatment with COL-3 ameliora ted this response. The wet/dry lung weight ratio was significantly greater (P < 0.05) in the LPS group (10.1 +/- 1.0 ratio) than in either the control (6.4 +/- 0.5 ratio) or LPS+COL-3 (7.4 +/- 0.6 ratio) group. Conclusions. A single prophylactic treatment with COL-3 prevented lung inju ry in our model of endotoxin-induced ARDS. The proposed mechanism of COL-3 is a synergistic inhibition of the terminal neutrophil effectors MMPs and N E. Similar to the universal practice of prophylaxis against gastric stress ulceration and deep venous thromboses in trauma patients, chemically modifi ed tetracyclines may likewise be administered to prevent acute lung injury in critically injured patients at risk of developing ARDS. (C) 2001 Academi c Press.