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，只有少数吸烟者会患上慢性阻塞性肺疾病，而且CS引起的肺部恶化的比率在不同的人之间有很大的差异。CS通过改变肺组织中蛋白水解酶/抗蛋白酶的平衡而诱发肺气肿。然而，CS发挥作用的机制和定义个体易感性的宿主因素却知之甚少。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COPD发生中的重要性，炎症改变蛋白水解酶和抗蛋白水解酶的能力，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，这些都没有定义。 我们最近建立了可诱导过表达(OE)转基因系统，并利用该系统在成年小鼠肺中过表达IL-13和/或γ-干扰素(IFN-γ)。单独来看，这两种细胞因子都会导致令人印象深刻的肺气肿。IL-13可使肺气肿迅速发生，并伴有粘液化生、巨噬细胞、淋巴细胞和富含嗜酸性粒细胞的炎症。在干扰素-γ小鼠中，肺气肿发生缓慢，与粘液化生无关，而与巨噬细胞和粒细胞丰富的炎症有关。同时表达干扰素-γ和IL-13的小鼠肺气肿的发生率协同增加。 我们推测：(1)IL-13和干扰素-γ单独或联合作用，激活了肺气肿发生的重要途径；(2)IL-13和/或干扰素-γ的作用是通过肺组织中不同的蛋白水解酶/抗蛋白酶平衡的改变来实现的；(3)干扰素-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)进一步明确IL-13 OE和干扰素-γOE小鼠及其杂交后代的表型和蛋白水解酶/抗蛋白酶的变化。 (2)鉴定IL-13/干扰素-γ诱导的蛋白水解酶/抗蛋白酶平衡改变在这些动物肺气肿发生中的重要性。 (3)探讨IL-13和/或干扰素-γ在CS诱导的小鼠肺气肿中的表达及作用。

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.