HyperresponsivenessDampens Airway Inflammation and Protectin D1 Is Generated in Asthma and

Protectins are newly identified natural chemical mediators that counter leukocyte activation to promote resolution of inflammation. In this study, we provide the first evidence for protectin D1 (PD1, 10 R ,17 S -dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) formation from docosahexaenoic acid in human asthma in vivo and PD1 counterregulatory actions in allergic airway inflammation. PD1 and 17 S -hydroxy-docosahexaenoic acid were present in exhaled breath condensates from healthy subjects. Of interest, levels of PD1 were significantly lower in exhaled breath condensates from subjects with asthma exacerba-tions. PD1 was also present in extracts of murine lungs from both control animals and those sensitized and aerosol challenged with allergen. When PD1 was administered before aeroallergen challenge, airway eosinophil and T lymphocyte recruitment were decreased, as were airway mucus, levels of specific proinflammatory mediators, including IL-13, cysteinyl leukotrienes, and PGD 2 , and airway hyperresponsiveness to inhaled methacholine. Of interest, PD1 treatment after aeroallergen challenge markedly accelerated the resolution of airway inflammation. Together, these findings provide evidence for endogenous PD1 as a pivotal counterregulatory signal in allergic airway inflammation and point to new therapeutic strategies for modulating inflammation in asthmatic lung. The Journal of Immunology, 2007, 178: 496–502.

[1]  C. Serhan,et al.  The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering* , 2005, Journal of Biological Chemistry.

[2]  John Savill,et al.  Resolution of inflammation: the beginning programs the end , 2005, Nature Immunology.

[3]  Charles N Serhan,et al.  A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. , 2005, The Journal of clinical investigation.

[4]  L. Palmer,et al.  Diminished lipoxin biosynthesis in severe asthma. , 2005, American journal of respiratory and critical care medicine.

[5]  B. Levy Lipoxins and lipoxin analogs in asthma. , 2005, Prostaglandins, leukotrienes, and essential fatty acids.

[6]  N. Maheshwari,et al.  A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense* , 2005, Journal of Biological Chemistry.

[7]  P. Henson Dampening inflammation , 2005, Nature Immunology.

[8]  S. Leeder,et al.  Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. , 2004, The Journal of allergy and clinical immunology.

[9]  P. Mukherjee,et al.  Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Uddin,et al.  Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway , 2004, Nature Immunology.

[11]  M. Regan,et al.  Association of cystic fibrosis with abnormalities in fatty acid metabolism. , 2004, The New England journal of medicine.

[12]  J. Bousquet,et al.  High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma. , 2003, Respiratory medicine.

[13]  Song‐Pyo Hong,et al.  Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression* , 2003, Journal of Biological Chemistry.

[14]  C. Serhan,et al.  Novel Docosatrienes and 17S-Resolvins Generated from Docosahexaenoic Acid in Murine Brain, Human Blood, and Glial Cells , 2003, The Journal of Biological Chemistry.

[15]  S. Spector,et al.  Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma? , 2003, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[16]  C. Serhan,et al.  Resolvins , 2002, The Journal of experimental medicine.

[17]  Eugene Y. Kim,et al.  Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4 , 2002, Nature Medicine.

[18]  S. Yamamoto,et al.  New induction of leukotriene A(4) hydrolase by interleukin-4 and interleukin-13 in human polymorphonuclear leukocytes. , 2000, Blood.

[19]  M. Sanak,et al.  Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. , 2000, The European respiratory journal.

[20]  S. Narumiya,et al.  Prostaglandin D2 as a mediator of allergic asthma. , 2000, Science.

[21]  M. Murray,et al.  Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. , 1999, Critical care medicine.

[22]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[23]  S. Wenzel,et al.  Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. , 1997, American journal of respiratory and critical care medicine.

[24]  Kwang Woo Kim,et al.  Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. , 1995, The Journal of allergy and clinical immunology.

[25]  J. Morrow,et al.  Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. , 1994, The Journal of biological chemistry.

[26]  S. Weiss,et al.  The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I) , 1994, The European respiratory journal.

[27]  D. Munafo,et al.  Leukotriene A4 hydrolase in human bronchoalveolar lavage fluid. , 1994, The Journal of clinical investigation.

[28]  S. McColl,et al.  Granulocyte-macrophage colony-stimulating factor enhances 5-lipoxygenase levels in human polymorphonuclear leukocytes. , 1994, Journal of immunology.

[29]  C. Salome,et al.  Factors associated with bronchial hyperresponsiveness in Australian adults and children. , 1992, The European respiratory journal.

[30]  E. Corey,et al.  Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils. , 1984, The Journal of clinical investigation.