Study of new therapy for COPD by regulation of inflammatory cytokines and oxidant stress

[背景]Caspase-1对IL-1家族细胞因子IL-1 β、IL-18和IL-33的成熟至关重要。我们最近报道了COPD患者血清IL-18水平与肺功能（%FEV_1）之间存在显著相关性（Imaoka, ERJ 2009）。转基因C57BL/6小鼠肺中成熟IL-18的组成性过量产生导致严重的肺气肿病变（Hoshino, AJRCCM 2007）。我们报道了氧化还原活性蛋白硫氧还蛋白1 （TRX1）在野生型C57BL/6小鼠中阻止弹性酶诱导的肺气肿的发生和进展（Kinoshita, BBRC 2007）。炎症细胞因子和氧化应激都可能参与COPD的病理过程。在这项研究中，我们研究了caspase-1在弹性酶诱导的COPD小鼠模型中的作用。【材料与方法】第0天，C57BL/6 caspase-1缺陷（KO）小鼠和对照野生型C57BL/6小鼠，通过腹腔注射硫喷钠（2.5 ~ 5mg /只）麻醉，并通过气管置入微喷雾（MicroSprayer, Penn-Century, Inc., Philadelphia， PA）。将50微升0.9%生理盐水（对照品）或50 μL溶于生理盐水的纯化猪胰腺弹性酶（PPE, 0.25 U）喷入气管。第21天处死小鼠。对肺组织及支气管肺泡灌洗液（BALF）进行组织病理学分析。[结果]计算机彩色图像分析显示，与对照野生型小鼠（39.9 +- 1.5 μm）相比，弹性酶处理的caspase-1 KO小鼠的平均肺泡弦长（30 +- 2.0μm）（每组n = 5）显著减少。此外，在弹性酶处理的caspase-1 KO小鼠中，BALF中的炎症细胞（每组n = 10）被显著阻止。【结论】本研究提示caspase-1的激活可能参与了COPD患者肺气肿变化和肺部炎症的发病机制。

[Background]Caspase-1 is essential to maturity of IL-1 family cytokines IL-1beta, IL-18 and IL-33. We have recently reported that a significant correlation exists between serum levels of IL-18 and pulmonary function (%FEV_1) in COPD patients (Imaoka, ERJ 2009). Constitutive overproduction of mature IL-18 in the lungs of transgenic C57BL/6 mice resulted in severe emphysema lesions (Hoshino, AJRCCM 2007). We reported that redox-active protein thioredoxin 1 (TRX1) prevented the development and progression of elastase-induced emphysema in wild type C57BL/6 mice (Kinoshita, BBRC 2007). Both inflammatory cytokines and oxidative stress may be involved in the pathology of COPD. In this study, we investigated the roles of caspase-1 in elastase-induced COPD mouse model.[Material and methods]On day 0, C57BL/6 caspase-1 deficient (KO) mice and control wild type C57BL/6 mice and was anesthetized by intraperitoneal administration of thiopental (2.5 to 5 mg/mouse), and a microspray (MicroSprayer, Penn-Century, Inc., Philadelphia, PA) was inserted through its trachea. Fifty microliters of 0.9% physiological saline (vehicle) or 50 μL of purified porcine pancreatic elastase (PPE, 0.25 U) dissolved in saline was sprayed into the trachea. Mice were sacrificed on day 21. Lung tissues and bronchoalveolar lavage fluid (BALF) were histopathologically analyzed.[Result]A computerized color image analysis revealed that the mean alveolar chord length (30 +- 2.0μm), n = 5 for each group) was significantly reduced in elastase-treated caspase-1 KO mice, when compared with control wild type mice (39.9 +- 1.5 μm). In addition, inflammatory cells in BALF of(n = 10 for each group) was significantly prevented in elastase-treated caspase-1 KO mice.[Conclusion]Our results suggest that activation of caspase-1 may contribute to the pathogenesis of emphysematous changes and pulmonary inflammations in COPD patients.