Study for therapy in COPD patients by regulating proinflammatory cytokine and oxidant stress

慢性阻塞性肺病是一种多种症状并存的疾病，已知这些症状会影响任何个体慢性阻塞性肺病患者的预后。常见的共存症状包括动脉硬化、高血压、肺心病和右心衰、其他心血管系统病变、高脂血症、糖尿病、骨质疏松症、消瘦和抑郁症。因此，COPD的治疗除了考虑其他共存条件外，还需要考虑肺部症状。我们之前报道过严重慢性阻塞性肺病患者的肺部炎症并没有因为戒烟而得到改善。在我们的研究中，我们发现细胞因子白细胞介素-18 （IL-18）在COPD患者肺部的肺泡巨噬细胞、CD8^+ T细胞以及细支气管和肺泡上皮中均有强烈表达。在小鼠中，肺中组成性IL-18的过量产生导致肺部炎症，伴有CD8 + T细胞、巨噬细胞、中性粒细胞和嗜酸性粒细胞的出现。老龄IL-18 Tg小鼠肺体积增大、严重肺气肿改变、右心室扩张、轻度肺动脉高压。基于这些发现，我们假设IL-18可能与COPD共存症状的发生/发展有关。我们之前在小鼠模型中确定硫氧还xin1 （TRX1）抑制弹性酶诱导的肺部炎症和肺气肿变化。我们将利用弹性酶诱导的肺气肿模型来确定TRX1是否代表了COPD共存症状的可能新治疗方法。

COPD is a disorder with several coexisting symptoms, and these symptoms are known to influence the prognosis of any individual COPD patient. Common coexisting symptoms include arterial sclerosis, hypertension, cor pulmonale and right heart failure, other cardiovascular system lesions, hyperlipemia, diabetes mellitus, osteoporosis, emaciation, and depression. Therefore, treatment of COPD needs to consider pulmonary symptoms in addition to other co-existing conditions.We previously reported that pulmonary inflammation in patients with severe COPD was not improved by the cessation of smoking. In our studies, we found that the cytokine Interleukin-18 (IL-18) was strongly expressed in alveolar macrophages, CD8^+ T cells, and both the bronchiolar and alveolar epithelia in the lungs of COPD patients. In mice, constitutive IL-18 overproduction in the lungs resulted in pulmonary inflammation with the appearance of CD8^+ T cells, macrophages, neutrophils, and eosinophils. Enlarged lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in aged IL-18 Tg mice. Based on these finding, we hypothesize that IL-18 may contribute to the onset / development of the coexistence symptoms of COPD. We previously determined that thioredoxin1 (TRX1) inhibits elastase-induced pulmonary inflammation and emphysematous changes in a mouse model. We will utilize the elastase-induced emphysema model in order to determine if TRX1 represents a possible new treatment of the coexisting symptoms in COPD.