Liu Jing-Nan, Suh Dong-Hyeon, Yang Eun-Mi, Lee Seung-Ihm, Park Hae-Sim, Shin Yoo Seob
Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
Exp Mol Med. 2014 Sep 12;46(9):e113. doi: 10.1038/emm.2014.55.
Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg(-1) simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4(+) cells and the CD4(+)/CD8(+) T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma.
尽管一些研究已经解释了他汀类药物的免疫调节作用，但这些分子的确切机制和治疗意义仍有待阐明。本研究不仅评估了辛伐他汀在卵清蛋白（OVA）特异性小鼠哮喘模型中的治疗潜力和抑制机制，还通过全面的文献综述试图阐明先前研究指出的未来方向。将BALB/c小鼠对OVA致敏，然后给予三次OVA激发。在每次激发日，在激发前注射40mg/kg(-1)辛伐他汀。在最后一次激发后评估气道反应性、支气管肺泡灌洗（BAL）液中的炎性细胞组成和细胞因子水平，并测定肺匀浆中的T细胞组成和黏附分子表达。与载体处理的小鼠相比，辛伐他汀的给药降低了气道反应性、气道炎性细胞数量以及BAL液中白细胞介素（IL）-4、IL-5和IL-13的浓度（P<0.05）。组织学上，辛伐他汀处理的小鼠肺组织中的炎性细胞和含黏液的杯状细胞数量也减少。流式细胞术显示，辛伐他汀处理显著降低了肺CD4(+)细胞的百分比和CD4(+)/CD8(+) T细胞比率（P<0.05）。辛伐他汀处理还降低了在匀浆肺组织（P<0.05）和人上皮细胞中测得的血管细胞黏附分子1和细胞间黏附分子1蛋白的表达。由于细胞黏附分子表达降低导致的T细胞流入减少是辛伐他汀减轻气道反应性和过敏性炎症的机制之一。对文献的严格综述以及我们的研究结果表明，辛伐他汀应作为过敏性哮喘的潜在治疗策略进一步开发。
