RGD Reference Report - Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. - Rat Genome Database

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Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection.

Authors: Bauer, CM  Zavitz, CC  Botelho, FM  Lambert, KN  Brown, EG  Mossman, KL  Taylor, JD  Stampfli, MR 
Citation: Bauer CM, etal., PLoS One. 2010 Oct 12;5(10):e13251.
RGD ID: 4891425
Pubmed: PMID:20967263   (View Abstract at PubMed)
PMCID: PMC2953496   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0013251   (Journal Full-text)

BACKGROUND: Chronic obstructive pulmonary disease is a progressive lung disease that is punctuated by periods of exacerbations (worsening of symptoms) that are attributable to viral infections. While rhinoviruses are most commonly isolated viruses during episodes of exacerbation, influenza viruses have the potential to become even more problematic with the increased likelihood of an epidemic. METHODOLOGY AND PRINCIPAL FINDINGS: This study examined the impact of current and potential pharmacological targets namely the systemic corticosteroid dexamethasone and the peroxisome proliferator-activated receptor-gamma agonist pioglitazone on the outcome of infection in smoke-exposed mice. C57BL/6 mice were exposed to room air or cigarette smoke for 4 days and subsequently inoculated with an H1N1 influenza A virus. Interventions were delivered daily during the course of infection. We show that smoke-exposed mice have an exacerbated inflammatory response following infection. While smoke exposure did not compromise viral clearance, precision cut lung slices from smoke-exposed mice showed greater expression of CC (MCP-1, -3), and CXC (KC, MIP-2, GCP-2) chemokines compared to controls when stimulated with a viral mimic or influenza A virus. While dexamethasone treatment partially attenuated the inflammatory response in the broncho-alveolar lavage of smoke-exposed, virally-infected animals, viral-induced neutrophilia was steroid insensitive. In contrast to controls, dexamethasone-treated smoke-exposed influenza-infected mice had a worsened health status. Pioglitazone treatment of virally-infected smoke-exposed mice proved more efficacious than the steroid intervention. Further mechanistic evaluation revealed that a deficiency in CCR2 did not improve the inflammatory outcome in smoke-exposed, virally-infected animals. CONCLUSIONS AND SIGNIFICANCE: This animal model of cigarette smoke and H1N1 influenza infection demonstrates that smoke-exposed animals are differentially primed to respond to viral insult. While providing a platform to test pharmacological interventions, this model demonstrates that treating viral exacerbations with alternative anti-inflammatory drugs, such as PPAR-gamma agonists should be further explored since they showed greater efficacy than systemic corticosteroids.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
CCL2HumanHuman Influenza  ISOCcl2 (Mus musculus)mRNA:increased expression:lungRGD 
CXCL2HumanHuman Influenza  ISOCxcl2 (Mus musculus)mRNA:increased expression:lungRGD 
Ccl2RatHuman Influenza  ISOCcl2 (Mus musculus)mRNA:increased expression:lungRGD 
Ccl2MouseHuman Influenza  IEP mRNA:increased expression:lungRGD 
Cxcl2RatHuman Influenza  ISOCxcl2 (Mus musculus)mRNA:increased expression:lungRGD 
Cxcl2MouseHuman Influenza  IEP mRNA:increased expression:lungRGD 


Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2) Cxcl2  (C-X-C motif chemokine ligand 2)

Genes (Mus musculus)
Ccl2  (C-C motif chemokine ligand 2) Cxcl2  (C-X-C motif chemokine ligand 2)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2) CXCL2  (C-X-C motif chemokine ligand 2)

Gene CCL13 C-C motif chemokine ligand 13 Homo sapiens