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.

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

“…Thus, the optimal antibiotic therapy in OHCA would cover both respiratory and enteric organisms, suppress bacterial growth (bacteriostatic), and would exhibit limited bactericidal activity limiting membrane breakdown and LPS release that would compound PAMP-mediated systemic inflammation and reperfusion injury. Of note, in addition to their bacteriostatic effects on gram-positive and gram-negative organisms, the non-antibiotic properties of the tetracycline class of antibiotics have garnered interest given their anti-inflammatory properties and protective effects toward lung injury in models of ischemia-reperfusion with sepsis (Roy, et al 2012). …”

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Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

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