Effects of a dual inhibitor of TNF-α and IL-1 on lipopolysaccharide-induced lung injury in rats

Purpose

In this study, we evaluated the effect of FR167653, which is a potent suppressant of TNF-α and IL-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats.

Methods

Male Sprague–Dawley rats weighing from 200 to 270 g were used. Subject animals in the LPS only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the LPS/FR group also received an infusion of FR167653 at 0.2 mg/kg/hour, commencing 30 min prior to the LPS injection and continuing for 5.5 hours.

Measurements and results

The LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by the 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 levels of TNF-α and IL-1β were 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 resulted in a decrease in the serum TNF-α and IL-1β levels that was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-α and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.