Treating Viral Exacerbations of Chronic Obstructive Pulmonary Disease: Insights from a Mouse Model of Cigarette Smoke and H1N1 Influenza Infection

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 pote...

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Vydané v:	PloS one Ročník 5; číslo 10; s. e13251
Hlavní autori:	Bauer, Carla M. T., Zavitz, Caleb C. J., Botelho, Fernando M., Lambert, Kristen N., Brown, Earl G., Mossman, Karen L., Taylor, John D., Stämpfli, Martin R.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 12.10.2010 Public Library of Science (PLoS)
Predmet:	Alveoli Animal models Animals Anti-inflammatory agents Avian flu Bacterial infections Biochemistry CC chemokine receptors CCR2 protein Chemokines Chemokines - metabolism Chronic infection Chronic obstructive lung disease Chronic obstructive pulmonary disease Cigarette smoke Cigarettes Corticoids Corticosteroids Cytokines Dexamethasone Disease Models, Animal Drugs Epidemics Exposure Genomes Health aspects House mouse Humans Immunization Infection Infections Infectious Diseases/Respiratory Infections Inflammation Inflammatory response Influenza Influenza A Influenza A virus Influenza A Virus, H1N1 Subtype - isolation & purification Influenza viruses Influenza, Human - complications Influenza, Human - drug therapy Influenza, Human - metabolism Influenza, Human - virology Lung diseases Medicine Mice Mice, Inbred C57BL Monocyte chemoattractant protein 1 Mutation Neutrophilia Obstructive lung disease Pathology Peroxisome proliferator-activated receptors Pharmacology Pioglitazone PPAR gamma - agonists Pseudomonas aeruginosa Pulmonary Disease, Chronic Obstructive - metabolism Pulmonary Disease, Chronic Obstructive - physiopathology Pulmonary Disease, Chronic Obstructive - virology Respiratory distress syndrome Respiratory Medicine/COPD and Allied Disorders Respiratory Medicine/Respiratory Infections Rhinovirus Rodents Smoke Smoking Smooth muscle Steroids Studies Swine flu Swine influenza Thiazolidinediones - pharmacology Thiazolidinediones - therapeutic use Viral infections Viruses Canada
ISSN:	1932-6203, 1932-6203
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Popis
Shrnutí:	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. 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. 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Conceived and designed the experiments: CMTB CCZ JDT MS. Performed the experiments: CMTB CCZ FMB KNL. Analyzed the data: CMTB CCZ FMB KNL. Contributed reagents/materials/analysis tools: EGB KLM. Wrote the paper: CMTB JDT MS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0013251