title: Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.
abstract: BACKGROUND
  Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation.
  
  
  OBJECTIVE
  Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma.
  
  
  METHODS
  Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry.
  
  
  RESULTS
  Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes.
  
  
  CONCLUSIONS
  Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Planagumà
authors.forename: Shamsah
authors.initials: S
authors.lastname: Kazani
authors.forename: Gautham
authors.initials: G
authors.lastname: Marigowda
authors.forename: Oliver
authors.initials: O
authors.lastname: Haworth
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.forename: Douglas
authors.initials: D
authors.lastname: Curran-Everett
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: William J
authors.initials: WJ
authors.lastname: Calhoun
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Jarjour
authors.forename: William W
authors.initials: WW
authors.lastname: Busse
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000328:Adult; D001249:Asthma / Q000097:blood / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D044045:Lipoxins / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*
chemical_list: C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid