Huang Tien-Yu, Chu Heng-Cheng, Lin Yi-Ling, Lin Chih-Kung, Hsieh Tsai-Yuan, Chang Wei-Kuo, Chao You-Chen, Liao Ching-Len
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Toxicol Appl Pharmacol. 2009 May 15;237(1):69-82. doi: 10.1016/j.taap.2009.02.026. Epub 2009 Mar 10.
In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.
除了具有抗菌活性外，米诺环素在多种疾病模型中还发挥抗炎作用。然而，米诺环素是否影响炎症性肠病的发病机制尚未确定。我们研究了米诺环素对实验性结肠炎的影响及其潜在机制。通过用葡聚糖硫酸钠（DSS）或三硝基苯磺酸（TNBS）处理诱导小鼠急性和慢性结肠炎，并从临床和组织学方面评估米诺环素对结肠损伤的影响。用米诺环素对小鼠进行预防性和治疗性处理可显著降低死亡率，并减轻DSS诱导的急性结肠炎的严重程度。从机制上讲，给予米诺环素可抑制诱导型一氧化氮合酶（iNOS）的表达和硝基酪氨酸的产生，抑制促炎细胞因子的表达，抑制基质金属蛋白酶（MMP）2、3、9和13升高的mRNA表达，降低结肠组织中的凋亡指数，并抑制DSS诱导的急性结肠炎小鼠血清中的一氧化氮产生。在DSS诱导的慢性结肠炎中，米诺环素治疗还可减轻体重减轻，改善结肠组织学，并阻断结肠组织中iNOS、促炎细胞因子和MMP的表达。同样，米诺环素可通过降低死亡率和抑制结肠组织中促炎细胞因子的表达来改善TNBS诱导的小鼠急性结肠炎的严重程度。这些结果表明，米诺环素可能通过抑制肠道组织中iNOS和MMP的表达来保护小鼠免受DSS和TNBS诱导的结肠炎。因此，米诺环素是治疗人类炎症性肠病的一种潜在药物。
