Substance P Modulates Colitis-Asscociated 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.

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis

“…However, in our experimental setting, the effect of MCH on myofibroblasts was moderate and required the presence of cofactors (42). This is not totally unexpected, given that, in other studies, substance P induces collagen production by CCD18-Co only in the presence of TGF-␤ and IGF-1 (25), bradykinin synergizes with TNF-␣ to induce expression of COX-2 in the same cells (48), and vasoactive intestinal peptide increases proliferation of primary colonic myofibroblasts only in the presence of platelet-derived growth factor (21). At the molecular level, this MCH requirement for costimulators could perhaps be explained by the fact that G protein-coupled receptors, like MCHR1, lack intrinsic kinase activity, and thus they need to transactivate growth factor receptors to convey mitogenic and growth signals (12).…”

Human Monoclonal Antibodies against Clostridium difficile Toxins A and B Inhibit Inflammatory and Histologic Responses to the Toxins in Human Colon and Peripheral Blood Monocytes

“…11752; Invitrogen, Carlsbad, CA). Quantitative PCRs were run in an ABI Prism 7700 Fast sequence detector system as previously described (26). The levels of mRNA were determined by using cataloged primers (Invitrogen) for human TNF-␣ (Hs00174128_m1), IL-1␤ (Hs01555410_m1), and 18S (Hs99999901_s1).…”

Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum

“…SP is expressed by SI-NETs and is one of the kinins potentially involved in flushing and carcinoid heart disease (Vinik et al 1990, Facco et al 1998, Niederle et al 2016. Furthermore, SP acts as a profibrotic cytokine in inflammatory fibrotic diseases such as intestinal and liver fibrosis and NK1R antagonist have been found to counteract the SP-induced fibrosis and secretion of profibrotic growth factors such as TGFβ (Koon et al 2010, Wan et al 2017. Also, SP has a proliferative and promigratory effect in cancer (Esteban et al 2006).…”