Substance P modulates colitis-associated fibrosis.

Abstract

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.

• Authors: Hon Wai Koon, David Shih, Iordanes Karagiannides, Dezheng Zhao, Zafeer Fazelbhoy, Tressia Hing, Hua Xu, Bao Lu, Norma Gerard, Charalabos Pothoulakis
• Journal: The American journal of pathology (Am J Pathol) Vol. 177 Issue 5 Pg. 2300-9 (Nov 2010) ISSN: 1525-2191 [Electronic] United States
• PMID: 20889569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid
• Bridged Bicyclo Compounds, Heterocyclic
• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1
• Transforming Growth Factor beta1
• Vimentin
• Substance P
• Insulin-Like Growth Factor I
• Trinitrobenzenesulfonic Acid
• Collagen
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (metabolism)
• Cell Line
• Cell Movement (drug effects)
• Colitis (chemically induced, metabolism, pathology)
• Collagen (metabolism)
• Colon (cytology, metabolism, pathology)
• Fibroblasts (cytology, drug effects, metabolism, pathology)
• Fibrosis
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Intestinal Mucosa (cytology, metabolism, pathology)
• Mice
• Mice, Knockout
• Neurokinin-1 Receptor Antagonists
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Neurokinin-1 (genetics, metabolism)
• Substance P (pharmacology)
• Transforming Growth Factor beta1 (metabolism)
• Trinitrobenzenesulfonic Acid (pharmacology)
• Vimentin (metabolism)