Selective sparing of goblet cells and Paneth cells in the intestine of methotrexate-treated rats

Proliferation, differentiation, and cell death were studied in small intest inal and colonic epithelia of rats after treatment with methotrexate. Days 1-2 after treatment were characterized by decreased proliferation, increase d apoptosis, and decreased numbers and depths of small intestinal crypts in a proximal-to-distal decreasing gradient along the small intestine. The re maining crypt epithelium appeared flattened, except for Paneth cells, in wh ich lysozyme protein and mRNA expression was increased. Regeneration throug h increased proliferation during days 3-4 coincided with villus atrophy, sh owing decreased numbers of villus enterocytes and decreased expression of t he enterocyte-specific genes sucrase-isomaltase and carbamoyl phosphate syn thase I. Remarkably, goblet cells were spared at villus tips and remained f unctional, displaying Muc2 and trefoil factor 3 expression. On days 8-10, a ll parameters had returned to normal in the whole small intestine. No metho trexate-induced changes were seen in epithelial morphology, proliferation, apoptosis, Muc2, and TFF3 immunostaining in the colon. The observed small i ntestinal sparing of Paneth cells and goblet cells following exposure to me thotrexate is likely to contribute to epithelial defense during increased v ulnerability of the intestinal epithelium.