title: Role of the inflammasome-caspase1/11-IL-1/18 axis in cigarette smoke driven airway inflammation: an insight into the pathogenesis of COPD.
abstract: BACKGROUND
  Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure. The disease is increasing in global prevalence and there is no effective therapy. A major step forward would be to understand the disease pathogenesis. The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD. This strongly suggests that the axis could be important in the pathogenesis of COPD. The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.
  
  
  METHODS
  We used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.
  
  
  RESULTS
  The inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α. This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia. Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia. Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g. E-Selectin.
  
  
  CONCLUSIONS
  This data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD.
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Suffwan
authors.initials: S
authors.lastname: Eltom
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, DTA Inflammation, Nutley, New Jersey, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Dubuis
authors.affiliation: University of Massachusetts, Division of Infectious Diseases & Immunology, Worcester, Massachusetts, United States of America.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001991:Bronchitis / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D058847:Inflammasomes; D007375:Interleukin-1; D020382:Interleukin-18; D014028:Tobacco Smoke Pollution; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1