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Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury.

Abstract
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.
AuthorsShreyas K Roy, Brian D Kubiak, Scott P Albert, Christopher J Vieau, Louis Gatto, Lorne Golub, Hsi-Ming Lee, Suraj Sookhu, Yoram Vodovotz, Gary F Nieman
JournalShock (Augusta, Ga.) (Shock) Vol. 37 Issue 4 Pg. 424-32 (Apr 2012) ISSN: 1540-0514 [Electronic] United States
PMID22258231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Tetracyclines
  • tetracycline CMT-3
Topics
  • Animals
  • Lung Injury (etiology)
  • Reperfusion Injury (complications)
  • Respiratory Distress Syndrome (prevention & control)
  • Sepsis (complications)
  • Tetracyclines (therapeutic use)

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