Critical role of P-selectin and lymphocyte function antigen-1 in radiation-induced leukocyte-endothelial cell interactions in the colon

PURPOSE: Radiation therapy is frequently used in treating different types of tumors, although associated with serious side effects, such as fibrosis and complicated diarrhea. This study was designed to define the adhesive mechanisms behind radiotherapy-induced leukocyte recruitment in the colon. METHODS: All mice, except control animals, were radiated with a single dose of 20 Gy. Mice were pretreated with an isotype-matched control antibody or a monoclonal antibody directed against P-selectin. In separate experiments, lymphocyte function antigen-1-deficient animals were used. Leukocyte rolling and firm adhesion were determined by use of inverted intravital fluorescence microscopy 16 hours after radiation. RESULTS: It was found that immunoneutralization of P-selectin reduced leukocyte rolling by 83 percent and adhesion by 87 percent in radiated mice. Moreover, radiation-induced leukocyte adhesion in LFA-1-deficient mice was decreased by 94 percent compared with wild-type animals. CONCLUSIONS: This study demonstrates that leukocyte rolling is mediated by P-selectin and that firm leukocyte adhesion is supported by lymphocyte function antigen-1 in radiation-induced enteritis. Moreover, P-selectin-dependent leukocyte rolling is a precondition for subsequent leukocyte adhesion in radiation-induced intestinal injury. Thus, targeting P-selectin and/or lymphocyte function antigen-1 may protect against pathologic inflammation in the colon induced by radiotherapy.