Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.

Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA
Proc Natl Acad Sci U S A. 2012 109 (31): 12692-7

PMID: 22802632 · PMCID: PMC3411985 · DOI:10.1073/pnas.1207816109

Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.

MeSH Terms (19)

Allergens Animals Antigens, Dermatophagoides Asthma Dinoprostone Intercellular Adhesion Molecule-1 Intramolecular Oxidoreductases Male Mice Mice, Knockout Pneumonia Prostaglandin-E Synthases Pulmonary Eosinophilia Receptors, Prostaglandin E, EP1 Subtype Receptors, Prostaglandin E, EP2 Subtype Receptors, Thromboxane Signal Transduction Thromboxane A2 Up-Regulation

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