P2X7 Receptor and Caspase 1 Activation Are Central to Airway Inflammation Observed after Exposure to Tobacco Smoke

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD.

The emerging role of transient receptor potential channels in chronic lung disease

“…These data are consistent with data suggesting that the cigarette smoke-induced inflammation is driven by the release of eATP resulting in P2X7 and subsequent inflammasome activation. Interestingly, the innate immune response was not altered in TRPV4 −/− mice challenged with an aerosol of LPS [138][139][140][141].…”

Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

“…Evidence for NLRP3 involvement in acute inflammation associated with CS exposure has been further studied in mouse models (39)(40). Nlrp3 2/2 mice displayed reduced caspase-1 activation, IL-18/IL-1b production, and neutrophil influx in the bronchoalveolar lavage (BAL) relative to wild-type mice after acute CS exposure (39).…”

“…Nlrp3 2/2 mice displayed reduced caspase-1 activation, IL-18/IL-1b production, and neutrophil influx in the bronchoalveolar lavage (BAL) relative to wild-type mice after acute CS exposure (39). Genetic deletion of the P2X7 receptor also reduced CS-induced caspase-1 activation, IL-1b release, and airway neutrophilia during acute CS exposure (40). Contrasting studies reported that pulmonary inflammation in response to acute CS exposure required IL-1b/a production and IL-1R, but was independent Recent studies indicate that both glucose metabolism and fatty acid (FA) synthesis may be linked to inflammasome activation (32,33).…”

The inflammasome in lung diseases

“…However, there is evidence of inflammasome activation, since levels of caspase-1 are increased in lung tissue after CS challenge in mice. Caspase-1 levels are also higher in lung tissue from COPD patients and smokers than from nonsmoking donors (19). Selective inhibition of caspase-1 significantly decreased inflammation after CS challenge in animal models (11).…”