title: Respiratory infections cause the release of extracellular vesicles: implications in exacerbation of asthma/COPD.
abstract: BACKGROUND
  Infection-related exacerbations of respiratory diseases are a major health concern; thus understanding the mechanisms driving them is of paramount importance. Despite distinct inflammatory profiles and pathological differences, asthma and COPD share a common clinical facet: raised airway ATP levels. Furthermore, evidence is growing to suggest that infective agents can cause the release of extracellular vesicle (EVs) in vitro and in bodily fluids. ATP can evoke the P2X7/caspase 1 dependent release of IL-1β/IL-18 from EVs; these cytokines are associated with neutrophilia and are increased during exacerbations. Thus we hypothesized that respiratory infections causes the release of EVs in the airway and that the raised ATP levels, present in respiratory disease, triggers the release of IL-1β/IL-18, neutrophilia and subsequent disease exacerbations.
  
  
  METHODS
  To begin to test this hypothesis we utilised human cell-based assays, ex vivo murine BALF, in vivo pre-clinical models and human samples to test this hypothesis.
  
  
  RESULTS
  Data showed that in a murine model of COPD, known to have increased airway ATP levels, infective challenge causes exacerbated inflammation. Using cell-based systems, murine models and samples collected from challenged healthy subjects, we showed that infection can trigger the release of EVs. When exposed to ATP the EVs release IL-1β/IL-18 via a P2X7/caspase-dependent mechanism. Furthermore ATP challenge can cause a P2X7 dependent increase in LPS-driven neutrophilia.
  
  
  CONCLUSIONS
  This preliminary data suggests a possible mechanism for how infections could exacerbate respiratory diseases and may highlight a possible signalling pathway for drug discovery efforts in this area.
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom.
authors: Suffwan
authors: S
authors: Eltom
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom.
authors: Nicole
authors: N
authors: Dale
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom.
authors: Kristof R G
authors: KR
authors: Raemdonck
authors: Novartis, Horsham, United Kingdom.
authors: Christopher S
authors: CS
authors: Stevenson
authors: Leukocyte Biology, Imperial College, London, United Kingdom.
authors: Robert J
authors: RJ
authors: Snelgrove
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom.
authors: Pradeep K
authors: PK
authors: Sacitharan
authors: Molecular Medicine, Imperial College, London, United Kingdom.
authors: Chiara
authors: C
authors: Recchi
authors: Institute of Ophthalmology, University College London, London, United Kingdom.
authors: Silene
authors: S
authors: Wavre-Shapton
authors: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, United Kingdom.
authors: Daniel F
authors: DF
authors: McAuley
authors: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, United Kingdom.
authors: Cecilia
authors: C
authors: O'Kane
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom; MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College, London, United Kingdom.
authors: Maria G
authors: MG
authors: Belvisi
authors: Respiratory Pharmacology, Imperial College, London, United Kingdom; MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College, London, United Kingdom.
authors: Mark A
authors: MA
authors: Birrell
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000150:complications / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000150:complications / Q000378:metabolism*
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020169:Caspases