Substance P modulates colitis-associated fibrosis.
Substance P (SP) and the neurokinin-1 receptor (NK-1R) are involved in the development of colitis and mucosal healing after colonic inflammation. We studied whether SP modulates colonic fibrosis by using a chronic model of trinitrobenzenesulfonic acid (TNBS)-induced colitis in wild-type (WT) and NK-1R-deficient (NK-1R KD) mice. We found increased mRNA expression levels of collagen, vimentin, and the fibrogenic factors transforming growth factor β1 and insulin-like growth factor 1 in the chronically inflamed colons of WT mice treated with repeated intracolonic TNBS administrations. Fibrosis in TNBS-treated mice was also evident immunohistochemically by collagen deposition in the colon. Treatment of TNBS-exposed WT mice with the NK-1R antagonist CJ-12255 reduced colonic inflammation, colonic fibrosis, fibroblast accumulation, and expression levels of the fibrogenic factors. NK-1R knockout mice chronically exposed to TNBS had similar colonic inflammation compared with WT, but reduced colonic fibrosis, fibroblast accumulation, and expression levels of fibrogenic factors. Immunohistochemical staining also showed co-localization of NK-1R with fibroblasts in inflamed colons of mice and in colonic mucosa of patients with Crohn's disease. Exposure of human colonic CCD-18Co fibroblasts to SP (10 nmol/L) increased cell migration. SP stimulated collagen synthesis in CCD-18Co fibroblasts in the presence of transforming growth factor β1 and insulin-like growth factor 1, and this effect was reduced by Akt inhibition. Thus, SP, via NK-1R, promotes intestinal fibrogenesis after chronic colitis by stimulating fibrotic responses in fibroblasts.
Koon
Hon Wai
HW
Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, MRL Building, Room 1240, 675 Charles E. Young Dr. South, Los Angeles, CA 90095, USA.
Shih
David
D
Karagiannides
Iordanes
I
Zhao
Dezheng
D
Fazelbhoy
Zafeer
Z
Hing
Tressia
T
Xu
Hua
H
Lu
Bao
B
Gerard
Norma
N
Pothoulakis
Charalabos
C
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism
C480026:6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D013373:Substance P; D007334:Insulin-Like Growth Factor I; D014302:Trinitrobenzenesulfonic Acid; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt