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.

• Authors: Suffwan Eltom, Christopher S Stevenson, Joseph Rastrick, Nicole Dale, Kristof Raemdonck, Sissie Wong, Matthew C Catley, Maria G Belvisi, Mark A Birrell
• Journal: PloS one (PLoS One) Vol. 6 Issue 9 Pg. e24097 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21915284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-18
• Interleukin-1beta
• Lipopolysaccharides
• Receptors, Purinergic P2X7
• Caspase 1

Topics

• Animals
• Caspase 1 (metabolism)
• Humans
• In Vitro Techniques
• Inflammation (chemically induced, metabolism)
• Interleukin-18 (metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (toxicity)
• Male
• Mice
• Receptors, Purinergic P2X7 (metabolism)
• Respiratory System (drug effects, metabolism)
• Smoking (adverse effects)