The role of the P2X7 receptor in cigarette smoke driven-inflammation associated with COPD

Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently, there are no effective therapies to stop the relentless progression of this disease. In the inflammatory milieu present in the lungs of animal models of, and human patients with COPD are increased levels of cytokines (IL-1β/IL-18) linked to activation of the NLRP3-Inflammasome. It has been postulated that exposure to CS leads to the release of endogenous danger signals (e.g. ATP) activating the NLRP3-Inflammasome via the P2X7 receptors driving the maturation and release of IL-1β and IL-18. The literature suggests that these cytokines are central to the chronic inflammation in the airway which drives the pathological changes seen in COPD. My hypothesis is that blockade of the P2X7 - NLRP3-Inflammasome pathway will attenuate the inflammation present in CS-induced airway inflammation. I developed an acute (3-day) model of COPD-like inflammation to investigate the role of the P2X7 receptor in this pathway. I 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. I used genetically modified mice lacking functional P2X7 receptors to show attenuation in caspase-1 activity, IL-1β release and airway neutrophilia in response to acute CS exposure but not LPS-induced airway inflammation. These findings were validated using a specific P2X7 receptor antagonist. Furthermore, I confirmed that the role of this pathway was not restricted to early stages of disease development by showing increased caspase-1 activity in lungs from a more chronic exposure to CS (28-day) and patients with COPD. This translational data suggests the P2X7-Inflammasome pathway plays an on-going role in disease pathogenesis. These results advocate the crucial role of the P2X7 – caspase-1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD