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.


METHODS
Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment.


METHODS
University animal laboratory.


METHODS
Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4.


METHODS
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).


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.
Nakayama
M
M
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, CA 94305-5236, USA.
Hasegawa
N
N
Oka
Y
Y
Lutzke
B
B
McCall
J M
JM
Raffin
T A
TA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015633:Extravascular Lung Water / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D007958:Leukocyte Count; D008168:Lung / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils; D009929:Organ Size; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D011506:Proteins / Q000032:analysis; D011552:Pseudomonas Infections / Q000150:complications; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018805:Sepsis / Q000150:complications*; D013552:Swine; D013556:Swine, Miniature; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000975:Antioxidants; D011281:Pregnatrienes; D011506:Proteins; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D010100:Oxygen; C053355:tirilazad