Substance P Modulates Colitis-Asscociated Fibrosis

被引：73

作者：

Koon, Hon Wai ^{[1
]}

Shih, David ^{[2
,3
]}

Karagiannides, Iordanes ^{[1
]}

Zhao, Dezheng ^{[4
,5
]}

Fazelbhoy, Zafeer ^{[1
]}

Hing, Tressia ^{[1
]}

Xu, Hua ^{[4
,5
]}

Lu, Bao ^{[6
]}

Gerard, Norma ^{[6
,7
]}

Pothoulakis, Charalabos ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Ctr Inflammatory Bowel Dis, Div Digest Dis, David Geffen Sch Med, Los Angeles, CA 90095 USA

[2] Cedars Sinai Med Ctr, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Immunobiol Res Inst, Los Angeles, CA 90048 USA

[4] Harvard Univ, Sch Med, Vasc Biol Res Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA

[5] Harvard Univ, Sch Med, Div Gastroenterol, Beth Israel Deaconess Med Ctr, Boston, MA USA

[6] Childrens Hosp, Ina Sue Perlmutter Lab, Div Pulm, Dept Pediat, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2010年 / 177卷 / 05期

基金：

美国国家卫生研究院;

关键词：

CLOSTRIDIUM-DIFFICILE TOXIN; INFLAMMATORY-BOWEL-DISEASE; EPIDERMAL-GROWTH-FACTOR; NEUROKININ-1 RECEPTOR ANTAGONIST; COLONIC EPITHELIAL-CELLS; PROTEIN-KINASE-C; NF-KAPPA-B; CROHNS-DISEASE; FIBROBLAST PROLIFERATION; INTESTINAL FIBROSIS;

D O I：

10.2353/ajpath.2010.100314

中图分类号：

R36 [病理学];

学科分类号：

100103 [病原生物学];

摘要：

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 beta 1 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 beta 1 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. (Am J Pathol 2010, 177:2300-2309; DOI: 10.2353/ajpath.2010.100314)

引用

页码：2300 / 2309

页数：10

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