title: 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.
authors.affiliation: Department of Surgery, Upstate Medical University, Syracuse, New York, USA. shreyas.roy@gmail.com
authors.forename: Shreyas K
authors.initials: SK
authors.lastname: Roy
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kubiak
authors.forename: Scott P
authors.initials: SP
authors.lastname: Albert
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Vieau
authors.forename: Louis
authors.initials: L
authors.lastname: Gatto
authors.forename: Lorne
authors.initials: L
authors.lastname: Golub
authors.forename: Hsi-Ming
authors.initials: HM
authors.lastname: Lee
authors.forename: Suraj
authors.initials: S
authors.lastname: Sookhu
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Gary F
authors.initials: GF
authors.lastname: Nieman
mesh_terms: D000818:Animals; D055370:Lung Injury / Q000209:etiology*; D015427:Reperfusion Injury / Q000150:complications*; D012128:Respiratory Distress Syndrome / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications*; D013754:Tetracyclines / Q000627:therapeutic use*
chemical_list: D013754:Tetracyclines; C117155:tetracycline CMT-3