雷帕霉素在溃疡性结肠炎患者中应用的临床价值评估

Rapamycin for treatment of ulcerative colitis

目的:研究雷帕霉素靶蛋白(mammalian targetof rapamycin,mTOR)通路抑制剂雷帕霉素在溃疡性结肠炎(ulcerative colitis,UC)中的抗炎及抑制癌变的临床价值评估.方法:我院55例UC患者,35例通过在口服美沙拉嗪的基础上加用雷帕霉素治疗10d后,对照组20例为口服美沙拉嗪的基础上加用安慰剂,观察电子结肠镜下溃疡面在治疗前后愈合比较,并检测治疗前后黏膜核因子-kB(nuclear factor-kB,NF-kB)、环氧化酶2(cyclooxygenase2,Cox2)表达变化,血清促炎因子肿瘤坏死因子-(tumor necrosis factoralpha,TNF-α)、白介素-6(interleukin-6,IL-6)及抑炎因子IL-10变化,同时检测治疗前后抑癌基因PTEN、PHLPP、Rb的表达变化.结果:实验组有1例患者出现口腔溃疡,2例患者因出现腹痛、排黏液脓血便加重而终止,余32例完成该研究,与对照组治疗比较,其中结肠镜下可见治疗后溃疡面明显减少,局部黏膜愈合较快;黏膜核因子NF-B(0.116±0.026)、C o x2(0.035±0.12)、促炎因子I L-6(13.25±3.78)表达量明显减低(P<0.05),抑炎因子IL-10(67.23±5.03)检测量增高(P<0.01),抑癌基因PTEN(0.212±0.18)、PHLPP(0.312±0.43)、R b(0.285±0.15)表达水平明显增高(P<0.01),血清TNF-(19.24±3.25)无统计学意义.结论:雷帕霉素作为免疫抑制剂联合美沙拉嗪可减轻UC炎症反应;并可通过抑制Akt/mTOR通路预防UC黏膜癌变.

AIM： To assess the effect of mammalian target of rapamycin （mTOR） pathway inhibitor rapamycin in the management of ulcerative colitis in terms of anti-inflammation and inhibition of malignant transformation. METHODS： Fifty patients with ulcerative colitis were enrolled, including 35 treated with rapamycin for 10 d on the basis of oral mesalazine and 20 treated with placebo on the basis of oral mesalazin. Ulcer healing was observed by elec- tron colonoscopy. The expression of nuclear factor-κB （NF-κB） and cyclooxygenase 2 （COX-2） in colonic mucosa and serum levels of proinflammatory factors tumor necrosis factor-alpha （TNF-α）, interleukin-6 （IL-6） and IL-10 were determined. In addition, expression of tumor suppressor genes PTEN, PHLPP and Rb was de- tected. RESULTS： In the experimental group, three pa- tients discontinued the treatment, including one due to oral ulcer and two due to abdominal pain and exacerbation of bloody stool. Thus, a total of 32 patients completed the study. Compared to the control group, ulcer surface was significantly reduced, the expression of colonic NF-KB and COX-2 and serum IL-6 were significantly de- creased （all P 〈 0.05）, and IL-10 level was signifi- cantly increased （P 〈 0.01） in the treatment group. In addition, the expression of PTEN, PHLPP and Rb was significantly increased in the treatment group compared to the control group （all P 〈 0.01）, although serum TNF-~ level showed no statistically significant difference between the two groups. CONCLUSION： Rapamycin plus mesalazine can relieve inflammation and prevent malignant transformation in ulcerative colitis possibly by inhibiting the Akt/mTOR pathway.