A tetracycline analog improves acute respiratory distress syndrome survival in an ovine model

Background: Acute respiratory distress syndrome (ARDS) mortality remains high with no effective pharmacotherapy available. A chemically modified tetracycline (COL-3) is a potent inhibitor of matrix metalloproteinases. Prophylactic COL-3 administration has been shown to be effective in ARDS treatment. In the present study, the therapeutic effect of COL-3, given shortly after injury, was investigated in an ovine ARDS model.

Methods: The ovine ARDS model was induced by combined 40% body area third-degree burn, smoke inhalation, and barotrauma injuries. The sheep were randomly assigned into two groups: control (10% Solutol, n = 5) or COL-3 (200 mg/m(2), n = 5). Intravenous administration of COL-3 or vehicle was performed 1 hour after the smoke and burn injury. When ARDS criteria were met (arterial partial pressure of oxygen to fraction of inspired oxygen ratio < 200) or no later than 24 hours after injury (if criteria not met), animals underwent the ARDS Network ventilation protocol. At 96 hours after injury or at animal death, lung pathologic processes were assessed.

Results: Administration of COL-3 improved hemodynamics and reduced carbon dioxide levels. Administration of COL-3 also significantly delayed ARDS development and prolonged survival time compared with the control group (20.4 + or - 3.8 hours versus 12.9 + or - 3.3 hours; 94.2 + or - 4.0 hours versus 58.6 + or - 26.4 hours; p < 0.05, respectively). Survival analysis showed a higher 96-hour survival from ARDS with COL-3 administration as compared with control (80% versus 20%; p < 0.05). Lung pathologic processes were also improved by COL-3. Plasma matrix metalloproteinase-2 level increased in control but not in COL-3-treated animals.

Conclusions: Our present study suggests that COL-3 may be an effective pharmacotherapy for ARDS treatment.