Selective Deficiency Of Prostaglandin E2 Uncovers A Dominant Effector Role For Thromboxane A2 In Allergen-induced Pulmonary Inflammation And Vascular Remodeling

Abstract

S U N D A Y 550 Selective Deficiency Of Prostaglandin E2 Uncovers A Dominant Effector Role For Thromboxane A2 In Allergeninduced Pulmonary Inflammation And Vascular Remodeling T. Liu, C. Feng, T. M. Laidlaw, W. Xing, S. Shen, G. Milne, J. A. Boyce; Department of Medicine, Harvard Medical School, Boston, MA, Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA, Department of Medicine and Pediatrics, Harvard Medical School, Boston, MA, Department of Pharmacology, Vanderbilt University, Nashville, TN. RATIONALE: Prostaglandin E2 (PGE2) has prominent anti-inflammatory and anti-fibrotic actions in the lung. Ptges mice are deficient in PGE2 and developed exaggerated pulmonary eosinophilia and hyperplasia of the pulmonary arteriolar smooth muscle compared with PGE2-sufficient controls when challenged intranasally with low doses of a house dust mite extract (Df). We hypothesized that both pulmonary eosinophilia and remodeling observed in the setting of selective PGE2 deficiency depend on thromboxane A2 (TXA2). METHODS: Double knockout mice lacking both ptges and T prostanoid (TP) receptor (ptges/tpr mice) were generated. After six challenges with Df, bronchial alveolar lavage fluid was collected and cell differential was counted; parabronchial lymph nodewas harvested and restimulated for cytokine generation analysis; and pulmonary pathological datawas collected. E prostanoid (EP) receptor-dependent blockade of intracellular adhesion molecule (ICAM)-1 induction by TP receptor stimulation was studied in vitro using human umbilical vein endothelial cells and antibody blocking of ICAM-1 was performed in vivo. RESULTS: The deletion of the TP receptor completely eliminated the increments in inflammation, vascular remodeling, effector cytokine generation, and ICAM-1 induction observed in the ptgesmice.Dysregulation of TP-dependent ICAM-1 induction was essential for the effects of PGE2 deficiency in vivo. In vitro studies demonstrated that TP receptor signaling was controlled hierarchically by EP1 and EP2 receptor-dependent pathways involving separate protein kinases. CONCLUSIONS: PGE2-mediated bronchoprotection involves prominent control of TP-dependent effector functions through a novel heterologous mechanism. TP receptor antagonism could be useful therapeutically in asthma associated with low levels of PGE2 production.