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

Abstract

INTRODUCTIONRadiation therapy for malignant pelvic, abdominal, or retroperitoneal diseases has the concurrent problem of radiation-induced bowel injury. Such injuries complicate current treatment regimens and preclude the use of larger radiation dosage and potentially more curable treatment schedules. The response of the microvasculature to radiation is widely regarded as the doselimiting factor for untoward effects to the intestine. Recent morphological and intravital microscopic studies have documented an early in¯ammatory response, appearing only a few hours after irradiation and characterized by leucocyte in®ltration into the irradiated organs. 1±3 This in¯ammatory response has been implicated in the vascular alterations that result from SUMMARY Background: In¯ammatory cells contribute to the acute and sub-acute sequelae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-lipoxygenase that suppresses NF±jB activation, has potent anti-in¯am-matory activity. Aims: To assess the effects of tepoxalin on radiationinduced in¯ammatory 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±jB 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, Nacetyl-L-cysteine, zileuton (lipoxygenase inhibitor), or vehicle.

Role of P‐selectin in radiation‐induced intestinal inflammatory damage

“…One is that the increase in leukocyte adhesion is not solely a consequence of an increase in P-selectin-mediated rolling; there is a release of proinflammatory mediators that directly affect firm adhesion of leukocytes. In that regard, platelet-activating factor [28] and leukotriene B 4 [29] have been shown to play an important role in mediating leukocyte adhesion after ionizing radiation, since inhibition of their synthesis or blockade of their receptors decreases the level of adhesion without affecting the rolling pool. These proinflammatory mediators may rapidly activate adhesion molecules on the leukocyte surface, namely ␤ 2 integrins, leading leukocytes to a sudden stop on the activated venular endothelium without previous rolling interactions.…”

Radiation-induced intestinal inflammation

“…Activation of NF-κB in nuclear extracts of intestinal samples in ir radiated rats was detectable 30 min after irradiation and was maximal at 60 min, with a progressive decline in the amount of this transcription factor in nuclear extracts over the following 60 min [17] . The radiation-induced inflammatory response is preceded by the NF-κB transcription factor that up-regulated ICAM-1 expression on endothelial cells [32,33] .…”

“…Confirmatory evidence has been provided showing that P-selectin expression is significantly up-regulated in response to abdominal irradiation, and this regulation is dose-and time-dependent [6] . However, lack of P-selectin does not afford protection against radiationinduced inflammatory intestinal alterations probably because leukocyte adhesion is not solely a consequence of an increase in P-selectin mediated rolling; there is a release of proinflammatory mediators like PAF [5] or LTB4 [17] that may directly affect firm leukocyte adhesion.…”

Sustained Inflammation Due to Nuclear Factor-Kappa B Activation in Irradiated Human Arteries

“…Previous in vitro studies suggest that radiation induces endothelial activation (15) characterized by activation of the transcription factor nuclear factor-kappa B (NF-B) (13,16), resulting in alterations in adhesion molecule expression (17,18) and cytokine and chemokine production (8). The activated endothelium is prone to atherosclerosis (19) and has prothrombotic properties, by promoting leukocyte-or plateletendothelial cell adherence (17,20), leukocyte infiltration into tissue (18,21), and thrombus formation (22).…”