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

Mitsuo Nakayama, Naoki Hasegawa, Yoshio Oka, Barry Lutzke, John M. McCall, Thomas A. Raffin

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)538-547
Number of pages10
JournalCritical Care Medicine
Volume26
Issue number3
DOIs
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

Miniature Swine
Acute Lung Injury
Sepsis
Neutrophils
Bronchoalveolar Lavage
Pulmonary Edema
Peroxidase
Tumor Necrosis Factor-alpha
Hemodynamics
Pseudomonas
Neutropenia
Pulmonary Hypertension
Weights and Measures
Hypotension
Pseudomonas aeruginosa
tirilazad
Lung
Bronchoalveolar Lavage Fluid
Laboratory Animals
Pentobarbital

Keywords

  • Acute lung injury
  • Lazaroid
  • Lipid peroxidation
  • Minipig
  • Neutrophil
  • Pseudomonas aeruginosar, oxygen radica
  • Sepsis
  • Thiobarbituric acid reactive material

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs. / Nakayama, Mitsuo; Hasegawa, Naoki; Oka, Yoshio; Lutzke, Barry; McCall, John M.; Raffin, Thomas A.

In: Critical Care Medicine, Vol. 26, No. 3, 1998, p. 538-547.

Research output: Contribution to journalArticle

Nakayama, Mitsuo ; Hasegawa, Naoki ; Oka, Yoshio ; Lutzke, Barry ; McCall, John M. ; Raffin, Thomas A. / Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs. In: Critical Care Medicine. 1998 ; Vol. 26, No. 3. pp. 538-547.
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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 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.",
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AU - Lutzke, Barry

AU - McCall, John M.

AU - Raffin, Thomas A.

PY - 1998

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N2 - 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.

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