Tepoxalin inhibits inflammation and microvascular dysfunction induced by abdominal irradiation in rats

Background: Inflammatory cells contribute to the acute and sub-acute sequelae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-lipoxygenase that suppresses NF-kappa B activation, has potent anti-inflammatory activity. Aims: To assess the effects of tepoxalin on radiation-induced inflammatory damage, and determine its mechanisms of action. Methods: Leucocyte rolling, adhesion and emigration, and albumin leakage were determined by intra-vital microscopy in rat mesenteric venules. NF-kappa B activation was measured by electrophoretic mobility shift assays, and endothelial intercellular adhesion molecule-1 expression by the radiolabelled antibody technique. Groups of irradiated rats were treated with tepoxalin, N-acetyl-L-cysteine, zileuton (lipoxygenase inhibitor), or vehicle. Results: Irradiated animals had a marked increase in the number of rolling, adherent and emigrated leucocytes in mesenteric venules, and in microvascular permeability. Tepoxalin prevented leucocyte adhesion and the increase in permeability after radiation. Tepoxalin did not inhibit radiation-induced NF-kappa B activation or intercellular adhesion molecule-1 up-regulation, while N-acetyl-L-cysteine, which attenuated NF-kappa B activation, had no effect on leucocyte recruitment. In contrast, tepoxalin inhibited the increase in leukotriene B-4 levels after radiation, and the anti-inflammatory effects of the drug were mimicked by zileuton. Conclusions: Tepoxalin affords significant protection against radiation-induced inflammation and microvascular dysfunction in splanchnic organs through a mechanism dependent on leukotriene synthesis inhibition.