Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis.
Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the "class switch" of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p<0.01), even in the absence of infection (p<0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p<0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA4/LTB4 ratio (p=0.01, r=0.66) and with percentage macrophage composition of the BAL fluid (p<0.001, r=0.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA4/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung.
National Children's Research Centre, Crumlin, Dublin, Ireland.
Fiona C
FC
Ringholz
National Children's Research Centre, Crumlin, Dublin, Ireland.
Paul J
PJ
Buchanan
National Children's Research Centre, Crumlin, Dublin, Ireland.
Donna T
DT
Clarke
National Children's Research Centre, Crumlin, Dublin, Ireland.
Roisin G
RG
Millar
Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
Michael
M
McDermott
National Children's Research Centre, Crumlin, Dublin, Ireland Midwestern Regional Hospital, Limerick, Ireland Centre for Interventions in Infection, Inflammation and Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland.
Barry
B
Linnane
Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Brian J
BJ
Harvey
National Children's Research Centre, Crumlin, Dublin, Ireland Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
Paul
P
McNally
National Children's Research Centre, Crumlin, Dublin, Ireland Institut National de la Santé et de la Recherche Médicale, U845, Faculté de Médecine Paris Descartes, Paris, France valerie.urbach@ncrc.ie.
Valerie
V
Urbach
D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000097:blood* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D007249:Inflammation; D017572:Leukotriene A4 / Q000737:chemistry; D007975:Leukotriene B4 / Q000737:chemistry*; D044045:Lipoxins / Q000737:chemistry*; D008137:Longitudinal Studies; D008168:Lung / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism
D000900:Anti-Bacterial Agents; D017572:Leukotriene A4; D044045:Lipoxins; C040527:lipoxin A4; D007975:Leukotriene B4; D001093:Arachidonate 15-Lipoxygenase