Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Chemotherapy or radiotherapy often cause mucosal damage in the gut (gut muc ositis) in cancer patients, As a step to investigate mechanisms underlying subsequent intestinal repair, we have examined the expression profiles of h epatocyte growth factor (HGF) and its receptor c-met, two molecules previou sly implicated in tissue repair, in comparison to the histopathological and proliferative changes in a rat model of methotrexate-induced small intesti nal mucositis. Histological analysis of the intestinal specimens revealed c rypt loss and villus atrophy with damage maximal on day 5 after methotrexat e injection, and normalization of mucosal structure commencing on day 6. Cr ypt cell proliferation was decreased dramatically on day 3, normalized on d ay 4 and up-regulated on days 5 and 6, HGF and c-met protein/mRNA expressio n was up-regulated between days 4 and 7, with the mRNA co-localizing to the crypt and lower villus epithelium, Therefore, following methotrexate injec tion, a decrease in crypt cell proliferation preceded histological damage, and conversely, crypt cell hyperproliferation preceded mucosal regeneration . Up-regulation of HGF and c-met coincided with crypt hyperproliferation an d mucosal recovery, suggesting a role for HGF in intestinal repair followin g acute injury. The crypt epithelial localization of HGF and c-met implies an autocrine or paracrine mechanism of HGF action. (C) 2000 Cancer Research Campaign.