Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats.
Proliferation, differentiation, and cell death were studied in small intestinal and colonic epithelia of rats after treatment with methotrexate. Days 1-2 after treatment were characterized by decreased proliferation, increased apoptosis, and decreased numbers and depths of small intestinal crypts in a proximal-to-distal decreasing gradient along the small intestine. The remaining crypt epithelium appeared flattened, except for Paneth cells, in which lysozyme protein and mRNA expression was increased. Regeneration through increased proliferation during days 3-4 coincided with villus atrophy, showing decreased numbers of villus enterocytes and decreased expression of the enterocyte-specific genes sucrase-isomaltase and carbamoyl phosphate synthase I. Remarkably, goblet cells were spared at villus tips and remained functional, displaying Muc2 and trefoil factor 3 expression. On days 8-10, all parameters had returned to normal in the whole small intestine. No methotrexate-induced changes were seen in epithelial morphology, proliferation, apoptosis, Muc2, and TFF3 immunostaining in the colon. The observed small intestinal sparing of Paneth cells and goblet cells following exposure to methotrexate is likely to contribute to epithelial defense during increased vulnerability of the intestinal epithelium.
Verburg
M
M
Laboratory of Pediatric Gastroenterology and Nutrition, Erasmus University and Sophia Children's Hospital, 3015GE Rotterdam, The Netherlands.
Renes
I B
IB
Meijer
H P
HP
Taminiau
J A
JA
Büller
H A
HA
Einerhand
A W
AW
Dekker
J
J
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy / Q000139:chemically induced; D015415:Biomarkers; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D020397:Goblet Cells / Q000166:cytology*; D020287:In Situ Nick-End Labeling; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000473:pathology; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D055262:Mucin-2; D009077:Mucins / Q000235:genetics; D009124:Muscle Proteins; D019879:Paneth Cells / Q000166:cytology*; D010455:Peptides; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012038:Regeneration / Q000502:physiology; D000071165:Trefoil Factor-3
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; C524628:Muc2 protein, rat; D055262:Mucin-2; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3; D008727:Methotrexate