EFFECTS OF TREATMENT WITH THE 21-AMINOSTEROID, U74389F, ON PULMONARY CYTOKINE EXPRESSION FOLLOWING HEMORRHAGE AND RESUSCITATION

Objective: To determine the effects of therapy with the antioxidant 21-aminosteroid, U74389F, on cytokine mRNA levels following hemorrhage and resuscitation. Design: Prospective, controlled animal study. Setting: University research laboratory. Subjects: Male bronchoalveolar lavage B/c (BALB/c) mice. Interventions: U74389F (10 mg/kg) in CS4 vehicle or CS4 vehicle alone, was administered intravenously to bronchoalveolar lavage B/c mice 15 mins before 30% blood volume hemorrhage, with resuscitation 60 mins later. Measurements and Main Results: Semiquantitative polymerase chain reactions were used to determine the effects of therapy with U74389F on cytokine mRNA levels among intraparenchymal pulmonary mononuclear cells, alveolar macrophages, and peripheral blood mononuclear cells obtained 2 hrs and 3 days after hemorrhage. In mice treated with U74389F, mRNA levels for interleukin (IL)-1 beta, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma were significantly decreased among intraparenchymal pulmonary mononuclear cells obtained 3 days, but not 2 hrs, after hemorrhage. No effects of therapy with U74389F were found in modulating posthermorrhage cytokine expression among alveolar macrophages or peripheral blood mononuclear cells. Conclusions: These studies demonstrate that treatment with U74389F, a 21-aminosteroid whose major activity is inhibition of lipid peroxidation due to the generation of reactive oxygen intermediates, significantly decreases hemorrhage-induced activation of proinflammatory cytokine expression among pulmonary cell populations. In addition, the present results, showing decreased expression of proinflammatory and immunoregulatory cytokines among intraparenchymal pulmonary mononuclear cells following treatment with U74389F, suggest that 21-aminosteroids may have clinical utility in preventing and/or modulating acute lung injury in the postinjury period.