title: Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors.
abstract: Cysteinyl leukotrienes (cysLTs) are bronchoconstricting lipid mediators that amplify eosinophilic airway inflammation by incompletely understood mechanisms. We recently found that LTC4, the parent cysLT, potently activates platelets in vitro and induces airway eosinophilia in allergen-sensitized and -challenged mice by a platelet- and type 2 cysLT receptor-dependent pathway. We now demonstrate that this pathway requires production of thromboxane A2 and signaling through both hematopoietic and lung tissue-associated T prostanoid (TP) receptors. Intranasal administration of LTC4 to OVA-sensitized C57BL/6 mice markedly increased the numbers of eosinophils in the bronchoalveolar lavage fluid, while simultaneously decreasing the percentages of eosinophils in the blood by a TP receptor-dependent mechanism. LTC4 upregulated the expressions of ICAM-1 and VCAM-1 in an aspirin-sensitive and TP receptor-dependent manner. Both hematopoietic and nonhematopoietic TP receptors were essential for LTC4 to induce eosinophil recruitment. Thus, the autocrine and paracrine functions of thromboxane A2 act downstream of LTC4/type 2 cysLT receptor signaling on platelets to markedly amplify eosinophil recruitment through pulmonary vascular adhesion pathways. The findings suggest applications for TP receptor antagonists in cases of asthma with high levels of cysLT production.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and.
authors.forename: Denise
authors.initials: D
authors.lastname: Garofalo
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and.
authors.forename: Chunli
authors.initials: C
authors.lastname: Feng
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and.
authors.forename: Juying
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and.
authors.forename: Howard
authors.initials: H
authors.lastname: Katz
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA 02115.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Laidlaw
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; and Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA 02115 jboyce@rics.bwh.harvard.edu.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Boyce
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D003545:Cysteine / Q000276:immunology*; D004802:Eosinophilia / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000276:immunology* / Q000494:pharmacology; D015289:Leukotrienes / Q000276:immunology*; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D015539:Platelet Activation / Q000276:immunology*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D000485:Allergens; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011982:Receptors, Prostaglandin; D019010:Vascular Cell Adhesion Molecule-1; C112381:cysteinyl-leukotriene; D018799:Intercellular Adhesion Molecule-1; D017997:Leukotriene C4; D013928:Thromboxane A2; D010047:Ovalbumin; D003545:Cysteine; D001241:Aspirin