Increased enterocyte apoptosis in inflamed areas of Crohn's disease.
OBJECTIVE
Because increased enterocyte apoptosis has been associated with the pathogenesis of several chronic inflammatory diseases, the aim of our study was to investigate epithelial cell death in Crohn's disease and the possible role of the Fas-Fas ligand system, E-cadherin, and matrix metalloproteinase-1 in modulating enterocyte apoptosis in this condition.


METHODS
Endoscopic ileal and colonic biopsy specimens were collected from macroscopically involved and uninvolved areas of 20 patients with Crohn's disease and 20 subjects who proved to have functional diarrhea. Diagnosis was established by clinical and pathologic criteria. Biopsy specimens were processed for traditional histology and for the immunohistochemical evaluation of Fas, Fas ligand, E-cadherin, Ki67 antigen, and matrix metalloproteinase-1 expression. For the in situ detection of apoptotic cells, terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end labeling was used.


RESULTS
The percentages of apoptotic enterocytes were higher in involved than in uninvolved areas of Crohn's disease patients and normal intestine. No significant difference was found between Crohn's disease uninvolved areas and normal intestine. In Crohn's disease, both enterocyte Fas and lamina propria mononuclear cell Fas ligand expression did not differ from controls. E-cadherin was strongly expressed by epithelium in both normal and inflamed intestine, except for the regenerative epithelium over the base of the ulcers, where a reduced E-cadherin expression was observed. The number of Ki67-positive proliferating epithelial cells did not differ either in involved or uninvolved areas of Crohn's disease patients compared with controls. A lamina propria overexpression of matrix metalloproteinase-1 was found in involved compared with uninvolved Crohn's disease areas and normal tissue, and a significant positive correlation between matrix metalloproteinase-1 expression and enterocyte apoptosis was found in Crohn's disease inflamed areas.


CONCLUSIONS
Enterocyte apoptosis is increased in involved areas of Crohn's disease. This increase is not mediated by a Fas-Fas ligand mechanism or by an abnormal E-cadherin distribution. Increased matrix metalloproteinase-1 release from lamina propria mononuclear cells might be one of the possible mechanisms responsible for the increased enterocyte apoptosis in Crohn's disease.
Di Sabatino
Antonio
A
Gastroenterology Unit, IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy.
Ciccocioppo
Rachele
R
Luinetti
Ombretta
O
Ricevuti
Laura
L
Morera
Raffaele
R
Cifone
Maria Grazia
MG
Solcia
Enrico
E
Corazza
Gino Roberto
GR
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D016022:Case-Control Studies; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology*; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D019014:fas Receptor / Q000378:metabolism
D015820:Cadherins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019394:Ki-67 Antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D020781:Matrix Metalloproteinase 1