Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs

Objective: To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis. Design: Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment. Setting: University animal laboratory. Subjects: Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO₂ of 0.4. Interventions: Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10⁶ colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO₂, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-α concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs). Measurements and Main Results: Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-α concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-α concentrations, or neutropenia. Conclusions: Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis- induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.