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

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

Research output: Contribution to journalArticle

180 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2771-2784
Number of pages14
JournalJournal of Clinical Investigation
Volume118
Issue number8
DOIs
StatePublished - Aug 1 2008

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Innate Immunity
Smoke
Tobacco Products
Viruses
Lung
eIF-2 Kinase
Human Influenza
Disease Progression
Eukaryotic Initiation Factor-2
Inflammation
Interleukin-23
Pathogen-Associated Molecular Pattern Molecules
Interleukin-18
Double-Stranded RNA
Emphysema
Virus Diseases
Interleukin-12
Chronic Obstructive Pulmonary Disease
Antiviral Agents
Pneumonia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. / Kang, Min Jong; Chun, Geun Lee; Lee, Jae Young; Dela Cruz, Charles S.; Chen, Zhijian J.; Enelow, Richard; Elias, Jack A.

In: Journal of Clinical Investigation, Vol. 118, No. 8, 01.08.2008, p. 2771-2784.

Research output: Contribution to journalArticle

Kang, Min Jong ; Chun, Geun Lee ; Lee, Jae Young ; Dela Cruz, Charles S. ; Chen, Zhijian J. ; Enelow, Richard ; Elias, Jack A. / Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 8. pp. 2771-2784.
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