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

Abstract

BackgroundChronic 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 FindingsThis 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 SignificanceThis 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.

The effect of peroxisome proliferator-activated receptor- ligands on in vitro and in vivo models of COPD

“…Inflammation in COPD is driven by a variety of stimuli, including oxidative stress, cytokines and tolllike receptor (TLR) stimulation by bacteria and viruses. Previous animal model data [10,31] and the current results therefore show evidence of efficacy for PPAR-c agonists in the prevention of inflammation caused by oxidative stress and/or TLR stimulation.…”

“…Rosiglitazone inhibits LPS-induced airway neutrophilia in an animal model [10], and here we show that rosiglitazone inhibits cigarette smoke-induced pulmonary neutrophilia in an animal model. H1N1 infection after 4 days of cigarette smoke exposure causes corticosteroid-resistant pulmonary inflammation in mice that is attenuated by pioglitazone [31]. This model of infection coupled with cigarette smoke-induced inflammation can be argued to resemble exacerbations of COPD.…”

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…It was concluded that the mechanism of these augmented inflammatory and remodeling responses is mediated by the MAVS/PKR/IL-18R␣/interferon (IFN)-␥ pathway. Several other studies (16,48) also confirm this enhanced inflammatory response in a CS-induced COPD mouse model. Although innate immunity plays an important role in COPD exacerbation-, CS-or virus-induced inflammatory and remodeling responses, the mechanisms that mediate these responses have not been completely defined.…”

Demographic distribution and transmission potential of influenza A and 2009 pandemic influenza A H1N1 in pilgrims

“…The demographic variables that could affect the distribution of influenza A infections in populations are gender [16][17][18][19], age [15], clinical signs [20], vaccination against flu [21], usage of antimicrobials [22,24], smoking habits [25,29], and ethnicity [30,31].…”