Epithelial proliferation, cell death, and gene expression in experimental colitis: alterations in carbonic anhydrase I, mucin MUC2, and trefoil factor 3 expression.
OBJECTIVE
To gain insight in intestinal epithelial proliferation, cell death, and gene expression during experimental colitis rats were treated with dextran sulfate sodium (DSS) for 7 days.


METHODS
Proximal and distal colonic segments were excised on days 2, 5, 7, and 28. Epithelial proliferation, cell death, enterocyte gene expression (carbonic anhydrase I (CA I) and goblet cell gene expression (mucin, MUC2; trefoil factor 3, TFF3) were studied immunohistochemically and biochemically.


RESULTS
Proliferative activity was decreased in the proximal and distal colon at the onset of disease (day 2). However, during active disease (days 5-7) epithelial proliferation was increased in the entire proximal colon and in the proximity of ulcerations in the distal colon. During DSS treatment the number of apoptotic cells in the epithelium of both colonic segments was increased. In the entire colon surface enterocytes became flattened and CA I negative during active disease (day 5-7). Additionally, CA I levels in the distal colon significantly decreased during this phase. In contrast, during the regenerative phase (day 28) CA I levels were restored in the distal colon and up-regulated in the proximal colon. During all disease phases increased numbers of goblet cells were observed in the surface epithelium of the entire colon. In the distal colon TFF3 expression extended to the bottom of the crypts during active disease. Finally, MUC2 and TFF3 expression was increased in the proximal colon during disease.


CONCLUSIONS
DSS affected the epithelium by inhibiting proliferation and inducing apoptosis. DSS-induced inhibition of CA I expression indicates down-regulation of specific enterocyte functions. Accumulation of goblet cells in the surface epithelium and up-regulation of MUC2 and TFF3 expression in the proximal colon underline the importance of goblet cells in epithelial protection and repair, respectively.
Renes
Ingrid B
IB
Department of Pediatrics, Erasmus Medical Center, Dr Molewaterplein 50, and Sophia Children's Hospital, 3015 GE Rotterdam, The Netherlands.
Verburg
Melissa
M
Van Nispen
Daniëlle J P M
DJ
Taminiau
Jan A J M
JA
Büller
Hans A
HA
Dekker
Jan
J
Einerhand
Alexandra W C
AW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D024401:Carbonic Anhydrase I / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology*; D003106:Colon / Q000201:enzymology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D020895:Enterocytes; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006133:Growth Substances / Q000235:genetics; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D055262:Mucin-2; D009077:Mucins / Q000187:drug effects / Q000235:genetics; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D015431:Weight Loss / Q000187:drug effects
D000998:Antiviral Agents; D015415:Biomarkers; D006133:Growth Substances; C524628:Muc2 protein, rat; D055262:Mucin-2; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D016264:Dextran Sulfate; D024401:Carbonic Anhydrase I; D001973:Bromodeoxyuridine