Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4).
The prevalence of asthma continues to increase and its optimal treatment remains a challenge. Here, we investigated the actions of lipoxin A(4) (LXA(4)) and its leukocyte receptor in pulmonary inflammation using a murine model of asthma. Allergen challenge initiated airway biosynthesis of LXA(4) and increased expression of its receptor. Administration of a stable analog of LXA(4) blocked both airway hyper-responsiveness and pulmonary inflammation, as shown by decreased leukocytes and mediators, including interleukin-5, interleukin-13, eotaxin, prostanoids and cysteinyl leukotrienes. Moreover, transgenic expression of human LXA(4) receptors in murine leukocytes led to significant inhibition of pulmonary inflammation and eicosanoid-initiated eosinophil tissue infiltration. Inhibition of airway hyper-responsiveness and allergic airway inflammation with a stable LXA(4) analog highlights a unique counter-regulatory profile for the LXA(4) system and its leukocyte receptor in airway responses. Moreover, our findings suggest that lipoxin and related pathways offer novel multi-pronged therapeutic approaches for human asthma.
Levy
Bruce D
BD
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
De Sanctis
George T
GT
Devchand
Pallavi R
PR
Kim
Eugene
E
Ackerman
Kate
K
Schmidt
Birgitta A
BA
Szczeklik
Wojciech
W
Drazen
Jeffrey M
JM
Serhan
Charles N
CN
D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001991:Bronchitis / Q000188:drug therapy*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D044045:Lipoxins; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011453:Prostaglandins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin
C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D018793:Interleukin-13; D015848:Interleukin-5; D015289:Leukotrienes; D044045:Lipoxins; D011453:Prostaglandins; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D016210:Methacholine Chloride