Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis
Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis
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DOI：
10.1152/ajpgi.00358.2010
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发表时间：
2011-01-01
影响因子：
4.5
通讯作者：
Sarna, Sushil K.
中科院分区：
文献类型：
--
作者：
Shi, Xuan-Zheng;Winston, John H.;Sarna, Sushil K.
克罗恩病和溃疡性结肠炎是临床、免疫学和形态学上不同形式的炎症性肠病 (IBD)。然而，这两种疾病的平滑肌功能都受到类似的损害，导致腹泻。我们在两种被认为代表这两种疾病的动物模型中测试了差异细胞、遗传和免疫机制介导平滑肌功能障碍的假设。我们使用三硝基苯磺酸（TNBS）和右旋糖酐硫酸钠（DSS）诱导的结肠炎症大鼠模型，其分别密切模仿克罗恩病和溃疡性结肠炎的临床和形态学特征。 DSS炎症最初在粘膜/粘膜下层引起氧化应激，然后传播到外肌层，损害平滑肌功能。外肌层未显示细胞因子/趋化因子增加。另一方面，TNBS炎症几乎同时诱导氧化应激，招募或激活免疫细胞，并在粘膜/粘膜下层和外肌层中产生细胞因子/趋化因子。细胞因子/趋化因子的产生与免疫细胞的招募和激活无关。因此，DSS炎症中平滑肌功能的受损主要是由于氧化应激，而TNBS炎症中平滑肌功能的受损是氧化应激和促炎细胞因子共同造成的。 DSS 炎症中平滑肌功能受损是由于兴奋-收缩耦合的 G α(q) 蛋白受到抑制。在 TNBS 炎症中，这是由于 Ca(v)1.2b 通道的 α(1C)1b 亚基、CPI-17 和 G α(q) 受到抑制。 TNBS 炎症会时间依赖性地增加外肌层中的 IGF-1 和 TGF-β。 IGF-1诱导平滑肌增生； IGF-1 和 TGF-β 均诱导肥大。总之，TNBS 和 DSS 都会诱导透壁炎症，尽管炎症介质类型不同。免疫细胞的招募或激活与炎症介质的产生强度不直接相关。 TNBS 和 DSS 炎症中的炎症介质针对不同的基因来损害平滑肌功能。
Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of G alpha(q) protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the alpha(1C)1b subunit of Ca(v)1.2b channels, CPI-17 and G alpha(q). TNBS inflammation increased IGF-1 and TGF-beta time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-beta induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of immune cells does not correlate directly with the intensity of generation of inflammatory mediators. The inflammatory mediators in TNBS and DSS inflammations target different genes to impair smooth muscle function.