Experimental
pharmacotherapies for the
acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified
tetracycline 3 (CMT-3), an
anti-inflammatory agent that blocks multiple
proteases and
cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of
inflammation-induced
lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal
sepsis-by placement of a fecal clot in the peritoneum, and (b)
ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups:
CMT-3 group (n = 7) received
CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a
CMT-3 vehicle (
carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial
bacteremia. Chemically modified
tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified
tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of
interleukin 1β (IL-1β),
tumor necrosis factor α,
IL-6,
IL-8, and
IL-10. This study presents a clinically relevant model of
lung injury in which
CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma
cytokines. Treatment of
sepsis patients with
CMT-3 could significantly reduce progression from
sepsis into ARDS.