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

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.

[1]  F. Martinez,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.

[2]  F. Di Virgilio,et al.  P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. , 2011, American journal of respiratory cell and molecular biology.

[3]  F. Di Virgilio,et al.  Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema , 2010, The Journal of Immunology.

[4]  F. Di Virgilio,et al.  Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. , 2010, American journal of respiratory and critical care medicine.

[5]  R. Polosa,et al.  Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. , 2009, Trends in pharmacological sciences.

[6]  G. Folkerts,et al.  ATP in the pathogenesis of lung emphysema. , 2009, European journal of pharmacology.

[7]  A. Churg,et al.  The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling. , 2009, American journal of respiratory cell and molecular biology.

[8]  C. Dinarello,et al.  Immunological and inflammatory functions of the interleukin-1 family. , 2009, Annual review of immunology.

[9]  H. Aizawa,et al.  Interleukin-18 production and pulmonary function in COPD , 2008, European Respiratory Journal.

[10]  G. Dubyak,et al.  Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages1 , 2007, The Journal of Immunology.

[11]  H. Young,et al.  Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13. , 2007, American journal of respiratory and critical care medicine.

[12]  D. Donnelly-roberts,et al.  Discovery of P2X7 receptor‐selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states , 2007, British journal of pharmacology.

[13]  M. Mishima,et al.  Neurotropin demonstrates cytoprotective effects in lung cells through the induction of thioredoxin-1. , 2007, American journal of respiratory cell and molecular biology.

[14]  B. Pedersen,et al.  Elevated Levels of IL-18 in Plasma and Skeletal Muscle in Chronic Obstructive Pulmonary Disease , 2007, Lung.

[15]  R. Homer,et al.  IL-18 Is Induced and IL-18 Receptor α Plays a Critical Role in the Pathogenesis of Cigarette Smoke-Induced Pulmonary Emphysema and Inflammation1 , 2007, The Journal of Immunology.

[16]  S. Mariathasan,et al.  Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation , 2007, Nature Reviews Immunology.

[17]  P. Calverley,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.

[18]  F. Sutterwala,et al.  NALP3: a key player in caspase-1 activation , 2006, Journal of endotoxin research.

[19]  F. Di Virgilio,et al.  The P2X7 Receptor: A Key Player in IL-1 Processing and Release1 , 2006, The Journal of Immunology.

[20]  M. Blackburn,et al.  Adenosine signaling in asthma and chronic obstructive pulmonary disease , 2006, Current opinion in pulmonary medicine.

[21]  M. Bours,et al.  Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. , 2006, Pharmacology & therapeutics.

[22]  C. Vogelmeier,et al.  [Pathogenesis of chronic obstructive pulmonary disease]. , 2006, Der Internist.

[23]  R. Stockley,et al.  COPD: current therapeutic interventions and future approaches , 2005, European Respiratory Journal.

[24]  M. Belvisi,et al.  Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF‐κB‐independent mechanism , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  J. Tichelaar,et al.  Interleukin-1beta causes pulmonary inflammation, emphysema, and airway remodeling in the adult murine lung. , 2005, American journal of respiratory cell and molecular biology.

[26]  D. Corry,et al.  An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema , 2004, PLoS medicine.

[27]  T Kendall Harden,et al.  Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. , 2003, Molecular pharmacology.

[28]  B. Beilin,et al.  Immune response in asymptomatic smokers , 2002, Acta anaesthesiologica Scandinavica.

[29]  C. Gabel,et al.  Absence of the P2X7 Receptor Alters Leukocyte Function and Attenuates an Inflammatory Response , 2002, The Journal of Immunology.

[30]  J. Keane,et al.  Severity of Elastase-Induced Emphysema Is Decreased in Tumor Necrosis Factor-α and Interleukin-1β Receptor-Deficient Mice , 2002, Laboratory Investigation.

[31]  U. Tylén,et al.  Neutrophil-associated activation markers in healthy smokers relates to a fall in DL(CO) and to emphysematous changes on high resolution CT. , 2001, Respiratory medicine.

[32]  Beverly H. Koller,et al.  Altered Cytokine Production in Mice Lacking P2X7Receptors* , 2001, The Journal of Biological Chemistry.

[33]  Alan D. Lopez.  THE GLOBAL BURDEN OF DISEASE 1990-2020 , 2001 .

[34]  I. P. Chessell,et al.  Pharmacological characterization of ATP‐ and LPS‐induced IL‐1β release in human monocytes , 1999 .

[35]  J. Barendregt,et al.  Global burden of disease , 1997, The Lancet.

[36]  D. Candinas,et al.  Loss of ATP Diphosphohydrolase Activity with Endothelial Cell Activation , 1997, The Journal of experimental medicine.

[37]  C. Gabel,et al.  Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. , 1994, The Journal of biological chemistry.