Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
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.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Tao
T
Liu
Tanya M
TM
Laidlaw
Chunli
C
Feng
Wei
W
Xing
Shiliang
S
Shen
Ginger L
GL
Milne
Joshua A
JA
Boyce
D000485:Allergens / Q000633:toxicity*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000633:toxicity*; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D000071876:Prostaglandin-E Synthases; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000276:immunology; D017482:Receptors, Thromboxane / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013928:Thromboxane A2 / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000485:Allergens; D039741:Antigens, Dermatophagoides; C090509:Icam1 protein, mouse; C545636:Ptger1 protein, mouse; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D017482:Receptors, Thromboxane; D018799:Intercellular Adhesion Molecule-1; D013928:Thromboxane A2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone