Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.

Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A(4) to LTC(4), the parent cysLT, through the terminal enzyme LTC(4) synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC(4) synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC(4) generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE(4) levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.

[1]  B. Samuelsson,et al.  Metabolism of arachidonic acid in polymorphonuclear leukocytes. Structural analysis of novel hydroxylated compounds. , 1979, The Journal of biological chemistry.

[2]  E. Corey,et al.  Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[3]  F. Fitzpatrick,et al.  Albumin stabilizes leukotriene A4. , 1982, The Journal of biological chemistry.

[4]  W. Owen,et al.  Regulation of human eosinophil viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts , 1987, The Journal of experimental medicine.

[5]  N. Meslier,et al.  Transcellular lipoxygenase metabolism between monocytes and platelets. , 1989, Journal of immunology.

[6]  A. Wardlaw,et al.  Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. , 1989, The American review of respiratory disease.

[7]  R. Dixon,et al.  Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. , 1990, The Journal of biological chemistry.

[8]  A. Ford-hutchinson,et al.  Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. , 1991, The American review of respiratory disease.

[9]  W. Owen,et al.  Eosinophil hematopoietins antagonize the programmed cell death of eosinophils. Cytokine and glucocorticoid effects on eosinophils maintained by endothelial cell-conditioned medium. , 1991, The Journal of clinical investigation.

[10]  J. Maclouf,et al.  Time-dependent utilization of platelet arachidonic acid by the neutrophil in formation of 5-lipoxygenase products in platelet-neutrophil co-incubations. , 1992, Biochimica et biophysica acta.

[11]  J. Morrow,et al.  Improved assay for the quantification of 11-dehydrothromboxane B2 by gas chromatography-mass spectrometry. , 1993, Journal of chromatography.

[12]  J. Morrow,et al.  Identification of non-cyclooxygenase-derived prostanoid (F2-isoprostane) metabolites in human urine and plasma. , 1993, The Journal of biological chemistry.

[13]  J. Drazen,et al.  Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. , 1994, The Journal of allergy and clinical immunology.

[14]  J. Morrow,et al.  Mass spectrometry of prostanoids: F2-isoprostanes produced by non-cyclooxygenase free radical-catalyzed mechanism. , 1994, Methods in enzymology.

[15]  C. Cerletti,et al.  Polymorphonuclear Leukocyte-Platelet Interaction: Role of P-Selectin in Thromboxane B2 and Leukotriene C4 Cooperative Synthesis , 1994, Thrombosis and Haemostasis.

[16]  H Nakajima,et al.  Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue , 1994, The Journal of experimental medicine.

[17]  J. Maclouf,et al.  Leukotriene C4 Formation by Transcellular Biosynthesis a , 1994, Annals of the New York Academy of Sciences.

[18]  B. Vargaftig,et al.  Antibody to very late activation antigen 4 prevents antigen-induced bronchial hyperreactivity and cellular infiltration in the guinea pig airways , 1994, The Journal of experimental medicine.

[19]  G. Freeman,et al.  Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Friend,et al.  Purification of human lung leukotriene C4 synthase and preparation of a polyclonal antibody. , 1995, American journal of respiratory and critical care medicine.

[21]  A. Sala,et al.  Release of Leukotriene A4 Versus Leukotriene B4 from Human Polymorphonuclear Leukocytes* , 1996, The Journal of Biological Chemistry.

[22]  A. Sousa,et al.  Effect of endobronchial aspirin challenge on inflammatory cells in bronchial biopsy samples from aspirin-sensitive asthmatic subjects. , 1996, Thorax.

[23]  E. Israel,et al.  Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group. , 1996, JAMA.

[24]  Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group. , 1996, JAMA.

[25]  AlbertSchömig,et al.  Induction of Cytokine Expression in Leukocytes by Binding of Thrombin-Stimulated Platelets , 1997 .

[26]  F. Neumann,et al.  Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. , 1997, Circulation.

[27]  L. Dubé,et al.  Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. , 1998, American journal of respiratory and critical care medicine.

[28]  M. Yamakido,et al.  Activation of platelets in bronchial asthma. , 1998, Chest.

[29]  S. Holgate,et al.  Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. , 1998, The Journal of clinical investigation.

[30]  D. Stevenson,et al.  Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. , 1999, The Journal of allergy and clinical immunology.

[31]  R. Murphy,et al.  Differential Metabolism of Exogenous and Endogenous Arachidonic Acid in Human Neutrophils* , 1999, The Journal of Biological Chemistry.

[32]  R. Simon,et al.  Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics. , 2000, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[33]  K. Austen,et al.  T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4. , 2001 .

[34]  P. O'Byrne,et al.  Inhaled leukotriene E(4), but not leukotriene D(4), increased airway inflammatory cells in subjects with atopic asthma. , 2001, American journal of respiratory and critical care medicine.

[35]  K. Austen,et al.  T Helper Cell Type 2 Cytokines Coordinately Regulate Immunoglobulin E–Dependent Cysteinyl Leukotriene Production by Human Cord Blood–Derived Mast Cells , 2001, The Journal of experimental medicine.

[36]  E. Israel,et al.  Effects of montelukast and beclomethasone on airway function and asthma control. , 2002, The Journal of allergy and clinical immunology.

[37]  M. Gawaz,et al.  A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation , 2002, The Journal of experimental medicine.

[38]  S. Harder,et al.  Clopidogrel but not aspirin reduces P‐selectin expression and formation of platelet‐leukocyte aggregates in patients with atherosclerotic vascular disease * , 2003, Clinical pharmacology and therapeutics.

[39]  K. Sladek,et al.  Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland , 2003, Allergy.

[40]  S. Raiden,et al.  Human Platelets Produce Granulocyte-Macrophage Colony-Stimulating Factor and Delay Eosinophil Apoptosis , 2003, Laboratory Investigation.

[41]  A. Higashi,et al.  Increase in urinary leukotriene B4 glucuronide concentration in patients with aspirin‐intolerant asthma after intravenous aspirin challenge , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[42]  J. Banks.  EFFECTS OF MONTELUKAST AND BECLOMETHASONE ON AIRWAY FUNCTION AND ASTHMA CONTROL , 2004 .

[43]  C. Page,et al.  Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation. , 2004, Blood.

[44]  C. Page,et al.  Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. , 2005, Blood.

[45]  P. Hordijk,et al.  Platelet binding to monocytes increases the adhesive properties of monocytes by up‐regulating the expression and functionality of β1 and β2 integrins , 2006, Journal of leukocyte biology.

[46]  K. Ley,et al.  Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. , 2006, The Journal of clinical investigation.

[47]  P. Hordijk,et al.  Platelet binding to monocytes increases the adhesive properties of monocytes by up-regulating the expression and functionality of beta1 and beta2 integrins. , 2006, Journal of leukocyte biology.

[48]  K. Austen,et al.  Expression of 5‐lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin‐intolerant asthma , 2006, The Journal of pathology.

[49]  J. Geng,et al.  P-selectin Cross-links PSGL-1 and Enhances Neutrophil Adhesion to Fibrinogen and ICAM-1 in a Src Kinase-Dependent, but GPCR-Independent Mechanism , 2007, Cell adhesion & migration.

[50]  K. Zen,et al.  Down-Regulation of Platelet Surface CD47 Expression in Escherichia coli O157:H7 Infection-Induced Thrombocytopenia , 2009, PloS one.

[51]  S. Paruchuri,et al.  Leukotriene E4–induced pulmonary inflammation is mediated by the P2Y12 receptor , 2009, The Journal of experimental medicine.

[52]  Richard W. Farndale,et al.  Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production , 2010, Science.

[53]  D. Lorrain,et al.  Pharmacodynamics and Pharmacokinetics of AM103, a Novel Inhibitor of 5‐Lipoxygenase‐Activating Protein (FLAP) , 2010, Clinical pharmacology and therapeutics.

[54]  N. Alenina,et al.  Platelet-derived serotonin links vascular disease and tissue fibrosis , 2011, The Journal of experimental medicine.

[55]  D. Mosher,et al.  Activation of beta1 integrins on blood eosinophils by P-selectin. , 2011, American journal of respiratory cell and molecular biology.