Deficient innervation characterizes intestinal strictures in a rat model of colitis.
Intestinal strictures are a common complication of Crohn's disease leading to serious consequences. With unknown etiology and cellular composition, strictures can be neither prevented nor reversed by current therapeutic strategies, and research has been limited by the lack of a well-developed animal model. We observed the sporadic occurrence of intestinal strictures at Day 35 in the TNBS rat model of colitis, which persisted beyond Day 90. Strictured tissue showed fusion, thickening, and disorganization of the smooth muscle layers. Immunocytochemistry revealed that all strictures were characterized by deficient innervation with a complete loss of intrinsic neurons, and a 92% loss of total axons per area. The number of alpha-smooth muscle actin-positive smooth muscle cells (SMC) increased in strictures, but immunolabeling showed phenotypic modulation of these cells, with the SMC phenotype (desmin-positive, vimentin-negative) entirely replaced by a myofibroblast phenotype (desmin-negative, vimentin-positive). Although cellular structure still predominated in the strictured regions, histochemistry showed increased extracellular matrix collagen, from 6 +/- 0.9% to 22 +/- 4% of total area. With previous evidence for neural loss in colitis, and in vitro studies showing neural regulation of smooth muscle cell (SMC) growth, we conclude that the regional loss of innervation may initiate tissue re-modeling that is characteristic of stricture formation.
Marlow
Stacey L
SL
Gastrointestinal Diseases Research Unit, Queen's University, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario, Canada K7L 5G2.
Blennerhassett
Michael G
MG
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D003251:Constriction, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000473:pathology*; D007415:Intestinal Obstruction / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009130:Muscle, Smooth / Q000294:innervation* / Q000473:pathology; D032390:Myoblasts, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014746:Vimentin / Q000378:metabolism
D015415:Biomarkers; D003893:Desmin; D014746:Vimentin; D003094:Collagen