Transforming growth factor β signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures

被引：196

作者：

Di Sabatino, A. ^{[5
]}

Jackson, C. L. ^{[6
]}

Pickard, K. M. ^{[6
]}

Buckley, M. ^{[6
]}

Rovedatti, L. ^{[5
]}

Leakey, N. A. B. ^{[1
]}

Picariello, L. ^{[2
]}

Cazzola, P. ^{[5
]}

Monteleone, G. ^{[3
,4
]}

Tonelli, F. ^{[2
]}

Corazza, G. R. ^{[5
]}

MacDonald, T. T. ^{[1
]}

Pender, S. L. ^{[6
]}

机构：

[1] Barts & London Queen Marys Sch Med & Dent, Ctr Infect Dis, Inst Cell & Mol Sci, London E1 2AT, England

[2] Univ Florence, Dept Clin Physiopathol, Florence, Italy

[3] Univ Roma Tor Vergata, Dipartimento Med Interna, Rome, Italy

[4] Univ Roma Tor Vergata, Ctr Eccellenza Studio Malattie Complesse & Multif, Rome, Italy

[5] Univ Pavia, Policlin San Matteo, Ctr Studio & Cura Malattie Infiammatorie Cron Int, Dept Med 1,Fdn IRCCS, I-27100 Pavia, Italy

[6] Univ Southampton, Div Infect Inflammat & Repair, Sch Med, Southampton, Hants, England

来源：

GUT | 2009年 / 58卷 / 06期

关键词：

INFLAMMATORY-BOWEL-DISEASE; TISSUE INHIBITOR; EXPRESSION; FIBROBLASTS; COLLAGEN; CELLS; GUT; STROMELYSIN-1; MIGRATION; METALLOELASTASE;

D O I：

10.1136/gut.2008.149096

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Background and Aims: In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor beta (TGF beta) is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix-degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). TGF beta signalling was investigated by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in patients with Crohn's disease (CD). Methods: Specimens were collected from macroscopically normal mucosa overlying strictured and non-strictured gut of patients with fibrostenosing CD. Isolated myofibroblasts were cultured with anti-TGF beta blocking antibody or TGF beta 1. TGF beta transcripts were analysed by quantitative reverse transcription-PCR (RT-PCR). Smad proteins and MMPs were determined by immunoblotting. MMP-12 activity was measured by a real-time MMP-12 activity assay. An in vitro wound-healing scratch assay was used to assess myofibroblast migration. Results: TGF beta transcripts, phosphorylated Smad2-Smad3 (pSmad2-3) and TIMP-1 proteins were higher in mucosa overlying strictures than in mucosa overlying non-strictured areas. In contrast, mucosa overlying strictured gut had lower expression of Smad7, MMP-12 and MMP-3. Myofibroblasts from mucosa overlying strictured gut showed higher TGF beta transcripts, a greater pSmad2-3 response to TGF beta, increased TIMP-1, lower Smad7, increased collagen production and reduced migration ability compared with myofibroblasts from mucosa overlying non-strictured gut. TGF beta blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared with strictured gut. Conclusions: Changes in TGF-beta signalling and MMP production were identified in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.

引用

页码：777 / 789

页数：13

共 46 条

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