Cigarette Smoke, RIG-like Helicases and Alveolar Remodeling

描述（由申请方提供）：暴露于香烟烟雾（CS）的患者中病毒感染的后果比未暴露/从未暴露的个体更严重。这在患有COPD的吸烟者中可见。它也见于其他健康的流感感染的吸烟者和呼吸道合胞病毒感染的儿童暴露于二手烟。我们比较了小鼠暴露于室内空气（RA）或CS的先天免疫反应。CS增强由Poly（I：C）（病毒先天免疫激动剂或PAMP）和流感病毒诱导的炎症、凋亡和重塑反应。这些答复是：（a）由RIG样解旋酶（RLH）抗病毒途径介导，（B）由RLH下游的效应级联介导，包括I型和II型干扰素、IL-18、双链RNA依赖性蛋白激酶（PKR）和真核起始因子-2（eIF 2），和（c）与2 '，5'-寡腺苷酸合酶（OAS）/内切核糖核酸酶L（RNaseL）抗病毒途径的激活相关。重要的是，暴露于CS的小鼠表现出Sca 1+上皮细胞修复反应，该反应通过病毒/病毒PAMP治疗而减弱。这就引出了下面的多重假设。假设1. CS增强肺中RLH介导的针对病毒/病毒PAMP的先天性应答。2.这种过度反应集中在呼吸道上皮中，在CS加病毒/病毒PAMP引起的炎症和重塑中起主要作用。3.在暴露于CS和病毒/病毒PAMPS的小鼠中，夸大的肺泡重塑是RLH先天免疫激活激活PKR/eIF 2（和2 '，5' OAS/RNase L抗病毒系统以同时诱导上皮损伤和抑制基于祖细胞的修复应答的能力的结果。具体目标。为了验证这一假设，我们建议：1。定义介导CS暴露小鼠中病毒/病毒PAMP效应的解旋酶。2.定义上皮和巨噬细胞RLH介导的先天性应答在CS+病毒/病毒PAMP效应发病机制中的作用。3.定义暴露于CS加病毒/病毒PAMP的小鼠中RLH激活调节上皮细胞损伤/凋亡的机制。4.定义RLH介导的先天激活调节暴露于CS加病毒/病毒PAMP的小鼠中基于祖细胞的修复反应的机制。公共卫生相关性：我们的研究表明，香烟烟雾增强抗病毒先天免疫肺反应，有助于病理性炎症和肺气肿。目前的研究将进一步确定介导这些反应的受体，它们的组织位置和这些关键相互作用的机制。

DESCRIPTION (provided by applicant): Viral infections have more severe consequences in patients exposed to cigarette smoke (CS) than in non/never-exposed individuals. This is seen in smokers with COPD. It is also seen in otherwise healthy, influenza-infected smokers and respiratory syncytial virus-infected children exposed to second hand smoke. We compared the innate immune responses in mice exposed to room air (RA) or CS. CS enhanced the inflammatory, apoptotic and remodeling responses that were induced by Poly(I:C) (a viral innate immunity agonist or PAMP) and influenza virus. These responses were: (a) mediated by the RIG-like helicase (RLH) antiviral pathway, (b) mediated by an effector cascade that is downstream of RLH and includes type I and II Interferons, IL-18, double-Stranded RNA-Dependent Protein Kinase (PKR) and eukaryotic initiation factor-2( (eIF2() and (c) associated with activation of the 2',5'-oligoadenylate synthase (OAS)/endoribonuclease L (RNaseL) antiviral pathway. Importantly, mice that had been exposed to CS manifest a Sca1+ epithelial cell repair response that was blunted by treatment with viruses/viral PAMPs. This led to the following multipart hypothesis. Hypothesis 1. CS augments RLH-mediated innate responses against viruses/viral PAMPs in the lung. 2. This exaggerated response is centered in the respiratory epithelium and plays a major role in the inflammation and remodeling caused by CS plus viruses/viral PAMPs. 3. The exaggerated alveolar remodeling that in mice exposed to CS and viruses/viral PAMPS is the result of the ability of RLH innate immune activation to activate both the PKR/eIF2( and the 2',5'OAS/RNase L antiviral systems to simultaneously induce epithelial injury and inhibit progenitor cell-based repair responses. Specific Aims. To test this hypothesis we propose to: 1. Define the helicases that mediate the effects of viruses/viral PAMPs in CS-exposed mice. 2. Define the role(s) of epithelial and macrophage RLH-mediated innate responses in the pathogenesis of the effects of CS plus viruses/viral PAMPs. 3. Define the mechanism by which RLH activation regulates epithelial cell injury/apoptosis in mice exposed to CS plus virus/viral PAMPs. 4. Define the mechanism by which RLH-mediated innate activation regulates progenitor cell based repair responses in mice exposed to CS plus virus/viral PAMPs. PUBLIC HEALTH RELEVANCE: Our studies demonstrate that cigarette smoke enhances antiviral innate immune pulmonary responses that contribute to pathologic inflammation and emphysema. The present studies will further define the receptors that mediate these responses, their tissue locations and the mechanisms of these critical interactions.