title: Physiological impact of abnormal lipoxin A₄ production on cystic fibrosis airway epithelium and therapeutic potential.
abstract: Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.
authors: National Children's Research Centre, Crumlin, Dublin 12, Ireland ; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Gerard
authors: G
authors: Higgins
authors: National Children's Research Centre, Crumlin, Dublin 12, Ireland ; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Fiona
authors: 0000-0001-5617-6441
authors: F
authors: Ringholz
authors: National Children's Research Centre, Crumlin, Dublin 12, Ireland.
authors: Paul
authors: 0000-0002-9055-2794
authors: P
authors: Buchanan
authors: National Children's Research Centre, Crumlin, Dublin 12, Ireland.
authors: Paul
authors: P
authors: McNally
authors: National Children's Research Centre, Crumlin, Dublin 12, Ireland ; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland ; Institut National de la Santé et de la Recherche Médicale, U845, Faculté de Médecine Paris Descartes, Site Necker, 156 rue Vaugirard, 75015 Paris, France.
authors: Valérie
authors: V
authors: Urbach
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D044045:Lipoxins / Q000096:biosynthesis* / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D044045:Lipoxins; C040527:lipoxin A4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate