Acute respiratory distress syndrome (ARDS) is the major cause of death in patients with severe smoke/burn injury. Activated neutrophils which release metalloproteinases (MMPs) are thought to play a role in this lung injury. The new non-antimicrobial tetracycline, COL-3, is an inhibitor of MMPs. Our goal, therefore, was to evaluate the therapeutic efficacy of COL-3 in our smoke/burn/barotrauma sheep ARDS model.
Under general anesthesia, sheep underwent smoke inhalation (4X12 breaths) and a third-degree burn injury (40% total body surface area). Ventilator –induced barotrauma (PS 40 cm H2O) was initiated immediately after the smoke/burn injury. Low tidal volume ventilation was applied when ARDS criteria (PaO2/FiO2 <200) was met or at 24 hr post injury if criteria were not met. Sheep were assigned to Vehicle (n=5, 10% Solutol HS 15) or the COL-3 group (n = 5, 200mg/m2 body surface). Vehicle or COL-3 was administered intravenously one hour after smoke/burn injury. At 96 hr or at time of death, the experiment was terminated and necropsy was performed.
ARDS criteria was met in 4/5 Vehicle and 4/5 COL-3 animals. The ARDS onset time was 13 ± 3.8 hr in Vehicle and 20.1 ± 3.6 hr in COL-3 group (P<0.05). Survival in the COL-3 sheep was significantly higher at 96 hours than in Vehicle (80%, 4/5 COL-3 vs 20%, 1/5 Vehicle). COL-3 animals also showed a longer survival compared with Vehicle (59 ± 26 hr vs 94 ± 4 hr, P<0.05). Lung wet-to-dry weight ratio was lower in COL-3 animals (5.840 ± 1.082 vs 7.428 ± 0.563). MMP-2 levels increased in Vehicle but not in COL-3 treated sheep. No significant toxicity was found in COL-3 treated compared to Vehicle animals.
Administration of COL-3 shortly after severe smoke-burn exposure delayed ARDS development and improved 96 hr survival in our ovine ARDS model.
Our findings show that COL-3 has a potential therapeutic benefit in the treatment of ARDS.
Xiaoqin Zhou, No Financial Disclosure Information; No Product/Research Disclosure Information