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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Postow, Lisa
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Zhou, Yang; Kang, Min-Jong; Jha, Babal Kant et al. (2013) Role of ribonuclease L in viral pathogen-associated molecular pattern/influenza virus and cigarette smoke-induced inflammation and remodeling. J Immunol 191:2637-46
Kang, Min-Jong; Choi, Je-Min; Kim, Bo Hye et al. (2012) IL-18 induces emphysema and airway and vascular remodeling via IFN-?, IL-17A, and IL-13. Am J Respir Crit Care Med 185:1205-17
Lee, Chun Geun; Ma, Bing; Takyar, Seyedtaghi et al. (2011) Studies of vascular endothelial growth factor in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 8:512-5
Ma, Bing; Dela Cruz, Charles S; Hartl, Dominik et al. (2011) RIG-like helicase innate immunity inhibits vascular endothelial growth factor tissue responses via a type I IFN-dependent mechanism. Am J Respir Crit Care Med 183:1322-35
Kang, Min-Jong; Lee, Chun Geun; Lee, Jae-Young et al. (2008) Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest 118:2771-84
Lee, Chun Geun; Kang, Hye-Ryun; Homer, Robert J et al. (2006) Transgenic modeling of transforming growth factor-beta(1): role of apoptosis in fibrosis and alveolar remodeling. Proc Am Thorac Soc 3:418-23