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

Crit Care Med. 1998 Mar;26(3):538-47. doi: 10.1097/00003246-199803000-00029.

Abstract

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 10(6) 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)-alpha 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-alpha 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-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Extravascular Lung Water / physiology
  • Hemodynamics / drug effects
  • Leukocyte Count
  • Lung / enzymology
  • Lung / pathology
  • Neutrophils
  • Organ Size
  • Oxygen / blood
  • Peroxidase / metabolism
  • Pregnatrienes / pharmacology*
  • Proteins / analysis
  • Pseudomonas Infections / complications
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / metabolism
  • Respiratory Distress Syndrome / pathology
  • Respiratory Distress Syndrome / physiopathology*
  • Sepsis / complications*
  • Swine
  • Swine, Miniature
  • Thiobarbituric Acid Reactive Substances
  • Tumor Necrosis Factor-alpha / analysis

Substances

  • Antioxidants
  • Pregnatrienes
  • Proteins
  • Thiobarbituric Acid Reactive Substances
  • Tumor Necrosis Factor-alpha
  • Peroxidase
  • Oxygen
  • tirilazad