Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Allergens / toxicity*
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Animals
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Antigens, Dermatophagoides / toxicity*
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Asthma / chemically induced
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Asthma / genetics
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Asthma / immunology*
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Dinoprostone / genetics
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Dinoprostone / immunology*
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / immunology
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / immunology
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Male
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Mice
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Mice, Knockout
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Pneumonia / chemically induced
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Pneumonia / genetics
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Pneumonia / immunology*
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Prostaglandin-E Synthases
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Pulmonary Eosinophilia / chemically induced
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Pulmonary Eosinophilia / genetics
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Pulmonary Eosinophilia / immunology*
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Receptors, Prostaglandin E, EP1 Subtype / genetics
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Receptors, Prostaglandin E, EP1 Subtype / immunology
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Receptors, Prostaglandin E, EP2 Subtype / genetics
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Receptors, Prostaglandin E, EP2 Subtype / immunology
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Receptors, Thromboxane / genetics
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Receptors, Thromboxane / immunology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Thromboxane A2 / genetics
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Thromboxane A2 / immunology*
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Allergens
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Antigens, Dermatophagoides
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Icam1 protein, mouse
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Ptger1 protein, mouse
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Receptors, Prostaglandin E, EP1 Subtype
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Thromboxane
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Intercellular Adhesion Molecule-1
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Thromboxane A2
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Intramolecular Oxidoreductases
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Prostaglandin-E Synthases
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Ptges protein, mouse
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Dinoprostone