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

Background: Inflammatory cells contribute to the acute and sub-acute sequel ae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-li poxygenase that suppresses NF-kappa B activation, has potent anti-inflammat ory 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 we re determined by intra-vital microscopy in rat mesenteric venules. NF-kappa B activation was measured by electrophoretic mobility shift assays, and en dothelial 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 microvascu lar permeability. Tepoxalin prevented leucocyte adhesion and the increase i n 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 e ffect on leucocyte recruitment. In contrast, tepoxalin inhibited the increa se in leukotriene B-4 levels after radiation, and the anti-inflammatory eff ects of the drug were mimicked by zileuton. Conclusions: Tepoxalin affords significant protection against radiation-ind uced inflammation and microvascular dysfunction in splanchnic organs throug h a mechanism dependent on leukotriene synthesis inhibition.