No abstract

Pathological features of both asthma and COPD coexist in some patients and this is termed asthma-COPD overlap (ACO). ACO is heterogeneous and patients exhibit various combinations of asthma and COPD features, making it difficult to characterise the underlying pathogenic mechanisms. There are no controlled studies that define effective therapies for ACO, which arises from the lack of international consensus on the definition and diagnostic criteria for ACO, as well as scant in vitro and in vivo data. There remain unmet needs for experimental models of ACO that accurately recapitulate the hallmark features of ACO in patients. The development and interrogation of such models will identify underlying disease-causing mechanisms, as well as enabling the identification of novel therapeutic targets and providing a platform for assessing new ACO therapies. Here, we review the current understanding of the clinical features of ACO and highlight the approaches that are best suited for developing representative experimental models of ACO.

Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2 À/À mice in cigarette smoke-induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2 À/À mice had increased airway neutrophils with decreased caspase-1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti-Ly6G in experimental COPD in wild-type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti-Ly6G treatment in Aim2 À/À mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase-1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti-Ly6G-mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase-1 in neutrophils.