Cigarette Smoke, RIG-like Helicases and Alveolar Remodeling

描述(申请人提供)：病毒感染对暴露于香烟烟雾(CS)的患者比非/从未接触过的人有更严重的后果。这在患有慢性阻塞性肺病的吸烟者身上可以看到。它也见于其他健康的、感染流感的吸烟者和接触二手烟的呼吸道合胞病毒感染的儿童。我们比较了暴露在室内空气(RA)或CS中的小鼠的先天免疫反应。CS可增强Poly(I：C)(一种病毒天然免疫激动剂或PAMP)和流感病毒诱导的炎症、凋亡和重塑反应。这些反应是：(A)由Rig-like Helicase(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依赖蛋白激酶(PKR)和真核细胞起始因子-2(eIF2()和(C)与2‘，5’-寡腺苷酸合酶(OAS)/内切核酸酶L(RNASL)抗病毒途径激活相关)。重要的是，暴露于CS的小鼠表现出Sca1+上皮细胞修复反应，这种反应因病毒/病毒PAMPs的治疗而变得迟钝。这导致了下面的多部分假设。假设1.CS在肺中增强RLH介导的针对病毒/病毒PAMP的先天反应。2.这种过度反应集中在呼吸道上皮细胞，在CS加病毒/病毒PAMPs引起的炎症和重塑中起主要作用。3.暴露于CS和病毒/病毒PAMPS的小鼠肺泡重构的夸大是由于rlh先天免疫激活能够激活PKR/eIF_2和2‘，5’-oas/核糖核酸酶L抗病毒系统，从而同时诱导上皮损伤和抑制祖细胞修复反应。明确的目标。为了验证这一假设，我们建议：1.定义在CS暴露的小鼠中介导病毒/病毒PAMP影响的解旋酶。2.明确上皮和巨噬细胞促性腺激素释放激素介导的先天反应在CS加病毒/病毒PAMPs作用机制中的作用(S)。3.明确RLH激活调节CS加病毒/病毒PAMPs致小鼠上皮细胞损伤/凋亡的机制。4.明确rlh介导的先天激活调节CS加病毒/病毒PAMPs暴露的小鼠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，香烟烟雾增强了抗病毒的先天免疫肺反应，这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、它们的组织位置以及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.