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 mucositis) in cancer patients. As a step to investigate mechanisms underlying subsequent intestinal repair, we have examined the expression profiles of hepatocyte growth factor (HGF) and its receptor c-met, two molecules previously implicated in tissue repair, in comparison to the histopathological and proliferative changes in a rat model of methotrexate-induced small intestinal mucositis. Histological analysis of the intestinal specimens revealed crypt loss and villus atrophy with damage maximal on day 5 after methotrexate injection, and normalization of mucosal structure commencing on day 6. Crypt cell proliferation was decreased dramatically on day 3, normalized on day 4 and up-regulated on days 5 and 6. HGF and c-met protein/mRNA expression was up-regulated between days 4 and 7, with the mRNA co-localizing to the crypt and lower villus epithelium. Therefore, following methotrexate injection, 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 and mucosal recovery, suggesting a role for HGF in intestinal repair following acute injury. The crypt epithelial localization of HGF and c-met implies an autocrine or paracrine mechanism of HGF action.
Xian
C J
CJ
Child Health Research Institute, University of Adelaide Department of Paediatrics, and Cooperative Research Centre for Tissue Growth and Repair, Australia.
Couper
R
R
Howarth
G S
GS
Read
L C
LC
Kallincos
N C
NC
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004751:Enteritis / Q000139:chemically induced*; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D008727:Methotrexate