Effects of a dual inhibitor of tumor necrosis factor-α and interleukin-1 on lipopolysaccharide-induced lung injury in rats:: Involvement of the p38 mitogen-activated protein kinase pathway

Objective: Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha. and interleukin (IL)-1 production, on lipopolysaccharide (LPS)induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653. Design: Prospective, randomized study. Setting: Animal research facility in a university. Subjects: Male Sprague-Dawley rats weighing 200-270 g. Interventions: All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg kg(-1) hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs. Measurements and Main Results: LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group, Serum concentrations of TNF-alpha. and IL-1 beta and plasma concentrations of thromboxane B-2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues. Conclusions: FR167653 administration decreased serum TNF-alpha and IL-1 beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.