| Chronic obstructive pulmonary disease (COPD) is a complex syndrome that poses a serious health threat to over 1.1 billion smokers worldwide. The primary risk factor for COPD is cigarette smoking. Although stable disease is punctuated by episodes of acute exacerbation that often hospitalize patients, the mechanisms underlying disease pathogenesis and progression are still poorly understood. Given that viruses are well established to exacerbate COPD, the purpose of this thesis was to broaden our understanding of the consequences of cigarette smoke exposure to antiviral responses. We hypothesized, in chapter 2 that type I interferon (IFN) responses, signaling cascades vital to the containment of viral infections, were impaired by cigarette smoke. We demonstrated that the immediate early, inductive, and amplification phases of the IFN response were impaired in smoke-exposed human lung fibroblast and epithelial cells. Given these findings, we hypothesized in chapter 3 that cigarette smoke would impair antiviral responses to H1N1 influenza A virus infection in mice. In contrast to the findings described in chapter 2, we demonstrated that viral clearance and IFN responses were not impaired in smoke-exposed mice, yet inflammation was exacerbated following infection. We demonstrated that a peroxisome proliferator-activated receptor (PPAR)-gamma agonist attenuated exaggerated inflammatory responses observed in smoke-exposed influenza-infected mice, while dexamethasone, a steroid, only partially attenuated those responses. To examine further if smoke-induced inflammation played a central role in the exaggerated inflammatory responses observed in smoke-exposed influenza-infected mice, in chapter 4, we demonstrated that interleukin (lL)-1alpha and its cognate receptor, IL-IR1, were critical for driving smoke-induced neutrophilic inflammation. Furthermore, IL-1alpha/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza-infected smoke-exposed mice. Taken together, the studies described in this thesis provide invaluable information that furthers our understanding of the progression and pathogenesis of COPD. Furthermore, the studies in chapters 3 and 4, respectively, highlight the potential for PPAR-gamma agonists and IL-1-targeted therapies, which may prove relevant for limiting inflammation and exacerbations in COPD. |
