Centro per la Prevenzione e Diagnosi della Malattia Celiaca, Fondazione IRCCS Cà-Granda Ospedale Maggiore Policlinico Milano, Milano, Italy.
Lab Invest. 2011 Mar;91(3):452-61. doi: 10.1038/labinvest.2010.186. Epub 2010 Nov 1.
Inflammatory bowel disease (IBD) represents a socially and clinically relevant disorder, characterized by intestinal chronic inflammation. Cystamine (CysN) is a multipotent molecule with healthy effects and, moreover, it is an inhibitor of transglutaminases (TGs), including the TG type 2 (TG2), an enzyme with pleiotropic functions, involved in different pathways of inflammation and central in the pathogenesis of some human disorders as the IBD. Our aim was to evaluate the effect of CysN in an IBD rat model. A total of 30 rats were divided into 4 groups: controls without treatment (CTR; n=7); receiving the 2,4,6-trinitrobenzene sulfonic acid enema (TNBS group; n=8); treated with TNBS enema plus oral CysN (TNBS-CysN group; n=8); treated with CysN (CysN group; n=7). After killing, bowel inflammation was evaluated applying specific scores. TG activity, TG2 and isopeptide bond immunohistochemical expression, and tumor necrosis factor-α (TNF-α) were evaluated in the colonic tissue, such as interleukin-6 (IL-6) serological levels (ELISA). TG2 was also evaluated on the luminal side of the colon by immunoautoradiography. Colonic samples from IBD patients were compared with animal results. TNBS-CysN group developed a less severe colitis compared with the TNBS group (macroscopic score 0.43±0.78 vs 3.28±0.95, microscopic score 6.62±12.01 vs 19.25±6.04, P<0.05, respectively) associated with a decrease of TG activity, TG2 and isopeptide bond immunohistochemical expression, TNF-α and IL-6 levels. No statistically significant differences were found between CysN and CTR groups. The colonic immunolocalization of TG2 was comparable in humans affected by IBD and TNBS-administered animals. This is the first demonstration that treatment with a CysN has an anti-inflammatory effect, reducing severity of colitis in a rat model. CysN could be tested as a possible treatment or co-treatment in IBD therapeutic trials.
炎症性肠病（IBD）是一种具有社会和临床意义的疾病，其特征为肠道慢性炎症。半胱胺（CysN）是一种具有多种健康效应的多功能分子，而且它还是转谷氨酰胺酶（TGs）的抑制剂，包括 TG 类型 2（TG2），一种具有多种功能的酶，参与炎症的不同途径，并且是一些人类疾病（如 IBD）发病机制的核心。我们的目的是评估 CysN 在 IBD 大鼠模型中的作用。总共 30 只大鼠被分为 4 组：无治疗的对照组（CTR；n=7）；接受 2,4,6-三硝基苯磺酸灌肠的大鼠组（TNBS 组；n=8）；接受 TNBS 灌肠加口服 CysN 的治疗组（TNBS-CysN 组；n=8）；接受 CysN 治疗的大鼠组（CysN 组；n=7）。处死大鼠后，采用特定评分评估肠道炎症。评估结肠组织中的 TG 活性、TG2 和异肽键免疫组织化学表达以及肿瘤坏死因子-α（TNF-α），并通过 ELISA 评估血清白细胞介素-6（IL-6）水平。通过免疫放射自显影评估结肠腔侧的 TG2。将 IBD 患者的结肠样本与动物结果进行比较。与 TNBS 组相比，TNBS-CysN 组大鼠的结肠炎程度较轻（宏观评分分别为 0.43±0.78 与 3.28±0.95，微观评分分别为 6.62±12.01 与 19.25±6.04，P<0.05），且 TG 活性、TG2 和异肽键免疫组织化学表达、TNF-α和 IL-6 水平均降低。CysN 组与 CTR 组之间无统计学差异。在 IBD 患者和接受 TNBS 治疗的动物中，TG2 的结肠免疫定位相似。这是首次证明用 CysN 治疗可产生抗炎作用，减轻大鼠模型中结肠炎的严重程度。CysN 可在 IBD 治疗试验中作为可能的治疗或联合治疗进行测试。
