Department of Pediatrics, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
J Pediatr Gastroenterol Nutr. 2010 Feb;50(2):132-9. doi: 10.1097/MPG.0b013e3181c61591.
Inflammatory bowel disease (IBD) is characterized by recurrent and severe gastrointestinal inflammation. Activation of inflammatory cells, such as TH17 lymphocytes, and/or deficiency of regulatory T cells (Treg) are responsible for the pathogenesis of IBD. As an acute phase reactant, heme oxygenase-1 (HO-1) has been shown to play an anti-inflammatory and immunomodulatory role in many disease processes. In this study, we used a dextran sulfate sodium (DSS)-induced murine colitis model to investigate the effect of upregulating HO-1 by hemin on the development of colonic inflammation.
The mice were enterically challenged with 4% DSS. In addition, some mice were intraperitoneally administered with hemin or Sn-protoporphyrin (SnPP) on days 0, 1, and 6 after DSS treatment. The severity of colitis was evaluated by daily monitoring of weight change and diarrhea. At the end of the experiment, the colon, spleen, and mesenteric lymph nodes were harvested for histology and various immunological assays.
Compared to control groups, DSS challenge markedly induced HO-1 expression in the colon epithelium. Upregulation of HO-1 by hemin was further correlated with attenuation of DSS-induced colitis. In contrast, inhibition of endogenous HO-1 by SnPP aggravated the colitis. To further assess the anti-inflammatory mechanisms, we examined whether hemin enhanced the proliferation of Treg cells and suppressed the production of interleukin (IL)-17. Flow cytometry analysis revealed that hemin markedly expanded the CD4 + CD25 + Foxp3+ Treg population. Moreover, hemin attenuated IL-17 and TH17-related cytokines. This inhibition coincided with the attenuation of DSS-induced colitis. Finally, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that hemin treatment markedly reduced programmed cell death of colonic epithelium, indicating that hemin exerts a modulatory effect on the induction of Treg, IL-17, and apoptosis.
These results demonstrate that upregulation of HO-1 by hemin ameliorated experimental colitis. Moreover, our study suggests a broader protective mechanism of hemin.
炎症性肠病（IBD）的特征是反复发作和严重的胃肠道炎症。炎症细胞的激活，如 TH17 淋巴细胞，和/或调节性 T 细胞（Treg）的缺乏，是 IBD 发病机制的原因。作为一种急性期反应物，血红素加氧酶-1（HO-1）已被证明在许多疾病过程中具有抗炎和免疫调节作用。在这项研究中，我们使用葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型来研究血红素上调 HO-1 对结肠炎症发展的影响。
用 4% DSS 对小鼠进行肠内挑战。此外，一些小鼠在 DSS 处理后第 0、1 和 6 天经腹腔给予血红素或锡原卟啉（SnPP）。通过每日监测体重变化和腹泻来评估结肠炎的严重程度。在实验结束时，采集结肠、脾脏和肠系膜淋巴结进行组织学和各种免疫测定。
与对照组相比，DSS 挑战显著诱导结肠上皮中 HO-1 的表达。血红素上调 HO-1 与 DSS 诱导的结肠炎的减轻进一步相关。相反，SnPP 抑制内源性 HO-1 加重了结肠炎。为了进一步评估抗炎机制，我们检查了血红素是否增强 Treg 细胞的增殖并抑制白细胞介素（IL）-17 的产生。流式细胞术分析显示，血红素显著扩增了 CD4+CD25+Foxp3+Treg 细胞群。此外，血红素减弱了 IL-17 和 TH17 相关细胞因子。这种抑制与 DSS 诱导的结肠炎的减轻一致。最后，末端脱氧核苷酸转移酶脱氧尿苷三磷酸末端标记测定显示，血红素处理显著减少了结肠上皮的程序性细胞死亡，表明血红素对 Treg、IL-17 和细胞凋亡的诱导具有调节作用。
这些结果表明，血红素上调 HO-1 可改善实验性结肠炎。此外，我们的研究表明血红素有更广泛的保护机制。
