Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis
Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis
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DOI：
10.1007/s00384-005-0793-7
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发表时间：
2006-12-01
影响因子：
2.8
通讯作者：
Geissler, Edward K.
中科院分区：
文献类型：
--
作者：
Farkas, Stefan;Hornung, Matthias;Geissler, Edward K.
背景：免疫抑制性钙调磷酸酶抑制剂，如环孢素（CsA），可用于严重溃疡性结肠炎的临床管理。然而，接受CsA治疗的患者有发生肾衰竭的风险，并且可能更容易患结肠癌。此外，严重的神经毒性和高血压是常见的问题。为了避免CsA的副作用，需要新的免疫抑制药物来治疗结肠炎。本研究的目的是在慢性结肠炎的实验模型中测试雷帕霉素抑制剂雷帕霉素的免疫抑制哺乳动物靶标，并将其有效性与CsA进行比较。方法：Balb/c小鼠经右旋糖酐硫酸钠灌胃4个周期后，建立慢性结肠炎模型。由于白细胞募集到肠道炎症部位对慢性结肠炎的发展至关重要，因此使用活体显微镜研究雷帕霉素和CsA对白细胞-内皮细胞相互作用和白细胞外渗的影响。为了评估结肠炎的程度，对组织切片进行了评价。结果：与对照组相比，雷帕霉素和环孢霉素均有效减少粘膜下小静脉中的白细胞粘附（> 60%）。此外，雷帕霉素，而不是CsA，减少（> 35%）粘膜中的白细胞外渗。雷帕霉素和CsA治疗均显著改善了组织学炎症评分。结论：我们的体内结果表明，雷帕霉素减少慢性结肠炎诱导过程中的白细胞粘附和外渗，并证明在减少实验性慢性结肠炎方面与CsA一样有效。这些结果支持在临床试验中使用雷帕霉素，以避免CsA治疗慢性结肠炎患者的严重副作用。
Background: Immunosuppressive calcineurin inhibitors, like cyclosporine (CsA), can be used for the clinical management of severe ulcerative colitis. However, patients treated with CsA are at a risk for developing kidney failure and may be more susceptible to colon cancer. Furthermore, severe neurotoxicity and hypertension are common problems. To avoid the side effects of CsA, new immunosuppressive drugs to treat colitis are needed. The aim of the present study was to test the immunosuppressive mammalian target of rapamycin inhibitor rapamycin in an experimental model of chronic colitis and to compare its effectiveness with CsA. Methods: Chronic colitis was established in Balb/c mice after four feeding cycles of dextran sodium sulfate. Because leukocyte recruitment to sites of intestinal inflammation is crucial for the development of chronic colitis, intravital microscopy was used to study the effect of rapamycin and CsA on leukocyte-endothelium interactions and leukocyte extravasation. To assess the degree of colitis, histological sections were evaluated. Results: Both rapamycin and cyclosporine effectively reduced leukocyte sticking (> 60%) in submucosal venules, as compared to controls. Furthermore, rapamycin, but not CsA, reduced (> 35%) leukocyte extravasation in the mucosa. Both rapamycin and CsA treatments significantly improved the histologic inflammation score. Conclusion: Our in vivo results demonstrate that rapamycin reduces leukocyte sticking and extravasation during chronic colitis induction and proves to be as effective as CsA at reducing experimental chronic colitis. These results support the use of rapamycin in clinical trials to avoid serious side effects of CsA therapy in chronic colitis patients.