Relative roles of ICAM-1 and VCAM-1 in the pathogenesis of experimental radiation-induced intestinal inflammation.

Abstract

Cell adhesion molecules mediate leukocyte recruitment into the irradiated organs; modulation of this process may protect from radiation damage. Our objective was to characterize the requirement for intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in intestinal inflammatory response after abdominal irradiation. Endothelial ICAM-1 and VCAM-1 expression was determined using radiolabeled antibodies in mice 24 h and 14 days after irradiation with 10 Gy, or sham radiation. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy, and the function of ICAM-1 and VCAM-1 in this process by using blocking antibodies and ICAM-1(-/-) mice. The number of adherent leukocytes significantly increased 24 h after irradiation and remained elevated at 14 days. Treatment with anti-ICAM-1 antibodies and ICAM-1 genetic deficiency significantly reduced leukocyte adhesion 24 h after irradiation. At 14 days after irradiation, both wild-type and ICAM-1(-/-) mice had an upregulation of VCAM-1, expression, and VCAM-1 immunoneutralization, but not ICAM-1 immunoneutralization, significantly reduced leukocyte adhesion. In ICAM-1(-/-) mice, regeneration of the intestinal epithelium was enhanced relative to wild-type mice. ICAM-1 plays a key role in leukocyte recruitment at early time points after abdominal irradiation, whereas VCAM-1 is the main molecular determinant of leukocyte recruitment at late time points.