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-kappaB activation, has potent anti-inflammatory activity.


OBJECTIVE
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-kappaB 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-kappaB activation or intercellular adhesion molecule-1 up-regulation, while N-acetyl-L-cysteine, which attenuated NF-kappaB activation, had no effect on leucocyte recruitment. In contrast, tepoxalin inhibited the increase in leukotriene B4 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.
Panés
J
J
Gastroenterology Department, Institut Clinic de Malalties Digestives, Barcelona, Spain. panes@medicina.ub.es
Mollà
M
M
Casadevall
M
M
Salas
A
A
Sans
M
M
Conill
C
C
Anderson
D C
DC
Roselló-Catafau
J
J
Granger
D N
DN
Piqué
J M
JM
D000005:Abdomen; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002448:Cell Adhesion; D004064:Digestive System / Q000098:blood supply; D007249:Inflammation; D007962:Leukocytes; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D010539:Permeability; D011720:Pyrazoles / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D007975:Leukotriene B4; C073135:tepoxalin