CMGH：抗菌肽或有助抑制炎性肠病患者机体纤维化

  发表在国际杂志Cellular and Molecular Gastroenterology and Hepatology上的一篇研究报告中，来自加利福尼亚大学的研究人员发现，一种由免疫细胞产生的天然蛋白或可抑制大肠炎患者发生纤维化和结瘢形成。

  克罗恩病，一种常见的炎性肠病（IBD），是儿童及青年个体中非常常见的一种难以治愈的顽疾。阻塞肠道的纤维化狭窄是克罗恩病常见的并发症，尽管当前可以通过手术将障碍移除，但疾病却会在其它部位复发，最后使得患者不得不在其一生中频繁手术进行治疗。

  研究者Wai Koon表示，我们发现一种名为抗菌肽的抗菌防御蛋白可以抑制临床前疾病模型中的肠纤维化，相关研究或为开发新型疗法抑制克罗恩病患者的再发性狭窄提供希望。抗菌肽是由很多细胞产生的抗菌蛋白家族的一员，此前研究显示抗菌肽具有抗炎性特点，而且可以抑制胶原的合成，而胶原则是纤维化伤疤的核心蛋白。

  这项研究中，研究人员想确定是否抗菌肽可以有效抑制胶原的合成以及肠道疾病患者机体的纤维化，研究者在两种临床前疾病模型及人类结肠成纤维细胞中研究了抗菌肽的作用效果；其中在一种克罗恩病模型中研究人员利用了三硝基苯磺酸进行治疗，其可以诱发小鼠机体出现慢性结肠炎及纤维化发生；而对结肠组织进行抗菌肽蛋白的灌输则可以在降低促炎性细胞因子(肿瘤坏死因子-α)产生的同时，也可以有效限制疾病模型体重的减少。

  最后研究者说道，抗菌肽促进伤口愈合及抑制纤维化的机制是我们未来研究的重点，本研究结果对于后期我们开发抑制克罗恩病患者机体再发性狭窄及纤维化的新型疗法提供了一定的帮助和思路。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

Antifibrogenic Effects of the Antimicrobial Peptide Cathelicidin in Murine Colitis-Associated Fibrosis
CMGH Cellular and Molecular Gastroenterology and Hepatology doi:10.1016/j.jcmgh.2014.08.001
Jun Hwan Yoo1, 2, Samantha Ho1, Deanna Hoang-Yen Tran1, Michelle Cheng1, Kyriaki Bakirtzi1, Yuzu Kubota1, Ryan Ichikawa1, Bowei Su1, Diana Hoang-Ngoc Tran1, Tressia C. Hing1, Irene Chang1, David Q. Shih3, Richard E. Issacson4, Richard L. Gallo5, Claudio Fiocchi6, Charalabos Pothoulakis1, Hon Wai Koon1, ,
Background & Aims
Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL-37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here, we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts.
Methods
C57BL/6J mice (n = 6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6–7 weeks) colitis with fibrosis. We administered mCRAMP peptide (5 mg/kg every 3 day, week 5–7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) intracolonically or intravenously, respectively. We then infected 129Sv/J mice with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp-expressing lentivirus (107 infectious units day 11) was administered intravenously.
Results
TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice compared with vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-β1 (TGF-β1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, which was reduced by LL-37 (3–5 μM) through a MAP kinase-dependent mechanism.
Conclusions
Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.