Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice
Min-Jong Kang, … , Richard Enelow, Jack A. Elias
Min-Jong Kang, … , Richard Enelow, Jack A. Elias
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2771-2784. https://doi.org/10.1172/JCI32709.
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Research Article

Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice

Abstract

Viral infections have more severe consequences in patients who have been exposed to cigarette smoke (CS) than in those not exposed to CS. For example, in chronic obstructive pulmonary disease (COPD), viruses cause more severe disease exacerbation, heightened inflammation, and accelerated loss of lung function compared with other causes of disease exacerbation. Symptomatology and mortality in influenza-infected smokers is also enhanced. To test the hypothesis that these outcomes are caused by CS-induced alterations in innate immunity, we defined the effects of CS on pathogen-associated molecular pattern–induced (PAMP-induced) pulmonary inflammation and remodeling in mice. CS was found to enhance parenchymal and airway inflammation and apoptosis induced by the viral PAMP poly(I:C). CS and poly(I:C) also induced accelerated emphysema and airway fibrosis. The effects of a combination of CS and poly(I:C) were associated with early induction of type I IFN and IL-18, later induction of IL-12/IL-23 p40 and IFN-γ, and the activation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor-2α (eIF2α). Further analysis using mice lacking specific proteins indicated a role for TLR3-dependent and -independent pathways as well as a pathway or pathways that are dependent on mitochondrial antiviral signaling protein (MAVS), IL-18Rα, IFN-γ, and PKR. Importantly, CS enhanced the effects of influenza but not other agonists of innate immunity in a similar fashion. These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses.

Authors

Min-Jong Kang, Chun Geun Lee, Jae-Young Lee, Charles S. Dela Cruz, Zhijian J. Chen, Richard Enelow, Jack A. Elias

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Figure 6

Roles of TLR3 in the interaction of CS and poly(I:C).

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Roles of TLR3 in the interaction of CS and poly(I:C). WT (+/+) mice and ...
WT (+/+) mice and mice with null mutations (–/–) of TLR3 were exposed to CS or RA (CS–) for 2 weeks and then given 1 or 4 doses of poly(I:C) (50 μg) or vehicle control. BAL total cell recovery after a single dose of poly(I:C) is illustrated in A. The levels of BAL IFN-γ (B), BAL total cell recovery (C), and alveolar remodeling (D) after 4 doses of poly(I:C) were also evaluated. The noted values represent the mean ± SEM of evaluations in a minimum of 5 mice. *P < 0.05.