Transgenic Cytokines in COPD

描述（由申请人提供）： 香烟烟雾（CS）是COPD发病的主要因素。 然而，只有少数吸烟者患上COPD，并且CS引起的肺恶化的比率在个体之间差异很大。 CS通过改变肺中的蛋白酶/抗蛋白酶平衡诱导肺气肿。 然而，CS发挥其作用的机制和定义个体易感性的宿主因素知之甚少。 炎症（巨噬细胞、淋巴细胞、嗜酸性粒细胞、中性粒细胞）在COPD中很常见。 炎症在产生COPD中的重要性、炎症改变蛋白酶和抗蛋白酶的能力以及不同类型的炎症在多大程度上可以解释COPD患者的不同表现尚未确定。 我们最近建立了一个诱导型过表达（OE）转基因系统，并使用该系统在成年小鼠肺中过表达IL-13和/或γ-干扰素（IFN-γ）。 单独两种细胞因子引起令人印象深刻的肺气肿。 使用IL-13时，肺气肿迅速发生，并与粘液化生和巨噬细胞、淋巴细胞和嗜酸性粒细胞丰富的炎症相关。 在IFN-γ小鼠中，肺气肿发生缓慢，与粘液化生无关，与巨噬细胞和粒细胞丰富的炎症有关。 同时表达IFN-γ和IL-13的小鼠肺气肿发生率协同增加。 我们假设：（1）IL-13和IFN-γ单独和组合激活肺中重要的肺气肿产生途径;（2）IL-13和/或IFN-γ的作用由肺蛋白酶/抗蛋白酶平衡的不同和可区分的改变介导;和（3）IFN-γ和IL-13在CS诱导的肺气肿的发病机制中起重要作用。 为了检验这一假设，我们建议： (1)进一步确定IL-13 OE和IFN-γ OE小鼠以及这些动物杂交后代的表型和蛋白酶/抗蛋白酶改变。 (2)描述IL-13 /IFN-γ诱导的蛋白酶/抗蛋白酶平衡改变在这些动物中观察到的肺气肿生成中的重要性。 (3)表征IL-13和/或IFN-γ在小鼠CS诱导的肺气肿中的表达和作用。

DESCRIPTION (provided by applicant): Cigarette smoke (CS) is a major factor in the pathogenesis of COPD. However, only a minority of smokers get COPD and the rate of CS-induced pulmonary deterioration differs greatly amongst individuals. CS induced emphysema via altering protease/antiprotease balance in the lung. However, the mechanisms by which CS exerts its effects and the host factors that define individual susceptibility are poorly understood. Inflammation (macrophages, lymphocytes, eosinophils, neutrophils) is common in COPD. The importance of inflammation in generating COPD, the ability of inflammation to alter proteases and antiproteases and, the degree to which different types of inflammation can account for different presentations of patients with COPD have not been defined. We recently established an inducible overexpression (OE) transgenic system and used this system to overexpress IL-13 and/or gamma-interferon (IFN-gamma) in the adult murine lung. Individually both cytokines caused impressive emphysema. With IL-13 the emphysema occurred rapidly and was associated with mucus metaplasia and macrophage, lymphocyte and eosinophil rich inflammation. In the IFN-gamma mouse, the emphysema occurred slowly, was not associated with mucus metaplasia and was associated with macrophage and granulocyte rich inflammation. Mice expressing both IFN-gamma and IL-13 had a synergistic increase in emphysema. We hypothesize that: (1) IL-13 and IFN-gamma alone and in combination, activate important emphysema generating pathways in the lung; (2) effects of IL-13 and/or IFN-gamma are mediated by distinct and differentiable alterations in pulmonary protease / antiprotease balance and (3) IFN-gamma and IL-13 play an important role in the pathogenesis of CS-induced emphysema. To test this hypothesis we propose to: (1) Further define the phenotype and protease / antiprotease alterations in IL-13 OE and IFN-y OE mice and progeny of crosses of these animals. (2) Characterize the importance of IL-13 / IFN-gamma-induced alterations in protease / antiprotease balance in the generation of the emphysema seen in these animals. (3) Characterize the expression and roles of IL-13 and/or IFN-gamma in murine CS-induced emphysema.