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PMID: 18583575 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.

American journal of respiratory and critical care medicine ·Vol. 178 ·No. 6 ·2008-09-15 ·Pages 574-82

Planagumà A, Kazani S, Marigowda G, Haworth O, Mariani TJ, Israel E, Bleecker ER, Curran-Everett D, Erzurum SC, Calhoun WJ, Castro M, Chung KF, Gaston B, Jarjour NN, Busse WW, Wenzel SE, Levy BD

Abstract

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. Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. 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. 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. 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.

MeSH Terms
Adult Asthma/blood,metabolism Bronchi/metabolism Bronchoalveolar Lavage Fluid/chemistry Female Flow Cytometry Humans Hydroxyeicosatetraenoic Acids/blood Lipoxins/biosynthesis,blood Male Middle Aged Polymerase Chain Reaction Receptors, Formyl Peptide/metabolism Receptors, Lipoxin/metabolism
Chemicals
FPR2 protein, human Hydroxyeicosatetraenoic Acids Lipoxins Receptors, Formyl Peptide Receptors, Lipoxin lipoxin A4 15-hydroxy-5,8,11,13-eicosatetraenoic acid
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Planagumà Anna
Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Kazani Shamsah
Marigowda Gautham
Haworth Oliver
Mariani Thomas J
Israel Elliot
Bleecker Eugene R
Curran-Everett Douglas
Erzurum Serpil C
Calhoun William J
Castro Mario
Chung Kian Fan
Gaston Benjamin
Jarjour Nizar N
Busse William W
Wenzel Sally E
Levy Bruce D
References (53)
53 references, click to expand
  1. Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness.
    J Immunol. 2007 Jan 1;178(1):496-502 PMID: 17182589
  2. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.
    Annu Rev Immunol. 2007;25:101-37 PMID: 17090225
  3. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors.
    J Exp Med. 1997 May 5;185(9):1693-704 PMID: 9151906
  4. Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels.
    Lipids. 1999;34 Suppl:S273-9 PMID: 10419177
  5. Epithelial cell PPAR[gamma] contributes to normal lung maturation.
    FASEB J. 2006 Jul;20(9):1507-9 PMID: 16720732
  6. 15-Lipoxygenase expression and 15(S)-hydroxyeicoisatetraenoic acid release and reincorporation in induced sputum of asthmatic subjects.
    J Allergy Clin Immunol. 2000 Apr;105(4):711-6 PMID: 10756220
  7. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition.
    Clin Exp Allergy. 2002 Nov;32(11):1558-65 PMID: 12569975
  8. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion.
    J Clin Invest. 1999 Aug;104(3):309-16 PMID: 10430612
  9. 15-lipoxygenase immunoreactivity in normal and in asthmatic airways.
    Am J Respir Crit Care Med. 1995 Apr;151(4):1201-4 PMID: 7697253
  10. Diminished lipoxin biosynthesis in severe asthma.
    Am J Respir Crit Care Med. 2005 Oct 1;172(7):824-30 PMID: 15961693
  11. Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage fluids obtained from patients with selected pulmonary diseases.
    Am Rev Respir Dis. 1990 Jun;141(6):1453-8 PMID: 2161628
  12. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids.
    Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):737-43 PMID: 9309987
  13. Interaction between integrin alpha9beta1 and vascular cell adhesion molecule-1 (VCAM-1) inhibits neutrophil apoptosis.
    Blood. 2006 Feb 1;107(3):1178-83 PMID: 16223772
  14. Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity.
    Clin Exp Allergy. 2007 Oct;37(10):1494-501 PMID: 17883729
  15. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.
    J Allergy Clin Immunol. 2007 Feb;119(2):405-13 PMID: 17291857
  16. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4).
    Nat Med. 2002 Sep;8(9):1018-23 PMID: 12172542
  17. Histochemical evidence for induction of arachidonate 15-lipoxygenase in airway disease.
    Am Rev Respir Dis. 1993 Apr;147(4):1024-8 PMID: 8466102
  18. Expression of 15-lipoxygenase type-1 in human mast cells.
    Biochim Biophys Acta. 2007 Sep;1771(9):1156-65 PMID: 17662651
  19. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor.
    J Exp Med. 1994 Jul 1;180(1):253-60 PMID: 8006586
  20. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury.
    J Immunol. 2005 Apr 15;174(8):5033-9 PMID: 15814734
  21. Acute passive anti-glomerular basement membrane nephritis in P-selectin-deficient mice.
    Kidney Int. 1996 May;49(5):1342-9 PMID: 8731099
  22. Discovery of a second 15S-lipoxygenase in humans.
    Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6148-52 PMID: 9177185
  23. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators.
    J Immunol. 2003 Dec 15;171(12):6856-65 PMID: 14662892
  24. Biosynthesis and biological activity of leukotriene B4.
    Clin Biochem. 1990 Oct;23(5):459-68 PMID: 2174753
  25. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.
    FASEB J. 2007 Dec;21(14):3877-84 PMID: 17625069
  26. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects.
    Science. 1987 Sep 4;237(4819):1171-6 PMID: 2820055
  27. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.
    Eur Respir J. 2003 Sep;22(3):470-7 PMID: 14516137
  28. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation.
    J Allergy Clin Immunol. 1995 Apr;95(4):843-52 PMID: 7722165
  29. The effects of lipoxin A4 on airway responses in asthmatic subjects.
    Am Rev Respir Dis. 1992 Jun;145(6):1281-4 PMID: 1595991
  30. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.
    Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):217-21 PMID: 1729692
  31. Severe asthma in adults: what are the important questions?
    J Allergy Clin Immunol. 2007 Jun;119(6):1337-48 PMID: 17416409
  32. Interleukin-4 induces 15-lipoxygenase-1 expression in human orbital fibroblasts from patients with Graves disease. Evidence for anatomic site-selective actions of Th2 cytokines.
    J Biol Chem. 2006 Jul 7;281(27):18296-306 PMID: 16675443
  33. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution.
    Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:433-55 PMID: 12432935
  34. The leukotriene B4 receptor (BLT1) is required for effector CD8+ T cell-mediated, mast cell-dependent airway hyperresponsiveness.
    J Immunol. 2006 Mar 1;176(5):3157-64 PMID: 16493075
  35. Leukotrienes as mediators of airway obstruction.
    Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 3):S193-200 PMID: 9817745
  36. Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound.
    J Allergy Clin Immunol. 2005 Jan;115(1):55-60 PMID: 15637547
  37. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.
    J Biol Chem. 2005 Apr 15;280(15):15267-78 PMID: 15708862
  38. The many faces of airway inflammation. Asthma and chronic obstructive pulmonary disease. Asthma Research Group.
    Am J Respir Crit Care Med. 1999 May;159(5 Pt 2):S41-63 PMID: 10228145
  39. Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury.
    Am J Pathol. 2006 Apr;168(4):1064-72 PMID: 16565483
  40. Eotaxin expression after segmental allergen challenge in subjects with atopic asthma.
    Am J Respir Crit Care Med. 2001 Jun;163(7):1669-75 PMID: 11401892
  41. Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha-induced IL-8 release.
    J Exp Med. 1998 Apr 20;187(8):1285-94 PMID: 9547339
  42. T-cell trafficking in asthma: lipid mediators grease the way.
    Nat Rev Immunol. 2004 Sep;4(9):711-24 PMID: 15343370
  43. Lipid mediator class switching during acute inflammation: signals in resolution.
    Nat Immunol. 2001 Jul;2(7):612-9 PMID: 11429545
  44. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.
    J Clin Invest. 1996 Nov 15;98(10):2201-8 PMID: 8941635
  45. Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics.
    Eur Respir J. 2000 Jul;16(1):44-9 PMID: 10933083
  46. Leukotriene bronchoconstriction induced by allergen and exercise.
    Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 2):S68-72 PMID: 10673230
  47. The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective.
    Clin Chem Lab Med. 2007;45(4):487-92 PMID: 17439326
  48. Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis.
    Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13375-80 PMID: 10557328
  49. Resolvin E1 and protectin D1 activate inflammation-resolution programmes.
    Nature. 2007 Jun 14;447(7146):869-74 PMID: 17568749
  50. Functional properties of guinea pig eosinophil leukotriene B4 receptor.
    J Immunol. 1991 Nov 1;147(9):3096-103 PMID: 1655904
  51. Regulation of cyclooxygenase-2 (COX-2) in rat renal cortex by adrenal glucocorticoids and mineralocorticoids.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15280-5 PMID: 10611376
  52. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils.
    J Exp Med. 1990 Nov 1;172(5):1451-7 PMID: 2172436
  53. Gene expression and immunolocalization of 15-lipoxygenase isozymes in the airway mucosa of smokers with chronic bronchitis.
    Am J Respir Cell Mol Biol. 2002 Dec;27(6):666-77 PMID: 12444026
Article Info
Journal
American journal of respiratory and critical care medicine
Abbr.
Am J Respir Crit Care Med
ISSN
1535-4970
DOI
10.1164/rccm.200801-061OC
Published
2008-09-15
Epub
2008-00-26
Pages
574-82
Language
English
Region
United States
NLM ID
9421642
PMCID
PMC2542432
Subset
IM
Grants
NCATS NIH HHS · UL1 TR000005 · United States
NIAID NIH HHS · AI068084 · United States
NHLBI NIH HHS · HL69349 · United States
External Links
PubMed source DOI: 10.1164/rccm.200801-061OC PMC Full Text View journal details
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