RESUMO
Atherosclerosis has an important inflammatory component. Macrophages accumulating in atherosclerotic arteries produce prostaglandin E(2) (PGE(2)), a main inflammatory mediator. Platelets express inhibitory receptors (EP(2), EP(4)) and a stimulatory receptor (EP(3)) for this prostanoid. Recently, it has been reported in ApoE(-/-) mice that PGE(2) accumulating in inflammatory atherosclerotic lesions might contribute to atherothrombosis after plaque rupture by activating platelet EP(3), and EP(3) blockade has been proposed to be a promising new approach in anti-thrombotic therapy. The aim of our investigation was to study the role of PGE(2) in human atherosclerotic plaques on human platelet function and thrombus formation. Plaque PGE(2) might either activate or inhibit platelets depending on stimulation of either EP(3) or EP(4), respectively. We found that the two EP(3)-antagonists AE5-599 (300 nM) and AE3-240 (300 nM) specifically and completely inhibited the synergistic effect of the EP(3)-agonist sulprostone on U46619-induced platelet aggregation in blood. However, these two EP(3)-antagonists neither inhibited atherosclerotic plaque-induced platelet aggregation, GPIIb/IIIa exposure, dense and alpha granule secretion in blood nor reduced plaque-induced platelet thrombus formation under arterial flow. The EP(4)-antagonist AE3-208 (1-3 µM) potentiated in combination with PGE(2) (1 µM) ADP-induced aggregation, demonstrating that PGE(2) enhances platelet aggregation when the inhibitory EP(4)-receptor is inactivated. However, plaque-induced platelet aggregation was not augmented after platelet pre-treatment with AE3-208, indicating that plaque PGE(2) does not stimulate the EP(4)-receptor. We found that PGE(2) was present in plaques only at very low levels (15 pg PGE(2)/mg plaque). We conclude that PGE(2) in human atherosclerotic lesions does not modulate (i.e. stimulate or inhibit) atherothrombosis in blood after plaque rupture.
Assuntos
Plaquetas/metabolismo , Estenose das Carótidas/metabolismo , Dinoprostona/metabolismo , Placa Aterosclerótica/metabolismo , Agregação Plaquetária , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Trombose/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Abortivos não Esteroides/farmacologia , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Plaquetas/patologia , Estenose das Carótidas/genética , Estenose das Carótidas/patologia , Dinoprostona/análogos & derivados , Dinoprostona/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Naftalenos , Fenilbutiratos , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Receptores de Prostaglandina E Subtipo EP3/agonistas , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP3/genética , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/genética , Ruptura Espontânea , Trombose/genética , Vasoconstritores/farmacologiaRESUMO
Derived from 2 yr of deliberations and community engagement, Medical Physics 3.0 (MP3.0) is an effort commissioned by the American Association of Physicists in Medicine (AAPM) to devise a framework of strategies by which medical physicists can maintain and improve their integral roles in, and contributions to, health care and its innovation under conditions of rapid change and uncertainty. Toward that goal, MP3.0 advocates a broadened and refreshed model of sustainable excellence by which medical physicists can and should contribute to health care. The overarching conviction of MP3.0 is that every healthcare facility can benefit from medical physics and every patient's care can be improved by a medical physicist. This large and expansive challenge necessitates a range of strategies specific to each area of medical physics: clinical practice, research, product development, and education. The present paper offers a summary of the Phase 1 deliberations of the MP3.0 initiative pertaining to strategic directions of the discipline primarily but not exclusively oriented toward the clinical practice of medical physics in the United States.