MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种慢性进行性疾病，可导致肺部血管重塑、血液含氧量低、右侧心力衰竭和死亡。预后不良和缺乏有效的多环芳烃疾病调节剂强调需要更好地了解疾病发病机制，以确定新的治疗方法。本文旨在探讨多环芳烃发生发展的分子机制。具体来说，我们将在生理和细胞水平上研究促炎细胞因子[巨噬细胞迁移抑制因子（MIF）]和甲状腺激素[甲状腺素（T4）]在PAH中先前未被认识到的临床相关相互作用的影响。我们已经确定MIF在PAH的发展和进展中是一个关键的介质，进一步，我们已经惊人地发现T4是MIF炎症活性的天然配体和抑制剂。我们假设，在PAH的发展过程中观察到的循环MIF的急剧增加改变了正常血浆中游离MIF的T4比值，这是肺动脉高压患者中甲状腺功能低下高发的基础。血浆中MIF和T4的修饰状态深刻地改变了这些分子与其各自细胞受体的相互作用，导致细胞内信号传导和血管细胞增殖的改变。我们概述了涉及临床研究、动物模型和体外评估的多方面方法。我们将研究PAH患者在疾病进展期间和标准化运动挑战前后的MIF-T4关系。我们将在肺血管重构的动物模型和细胞水平上进一步研究这些分子之间的相互关系，以更好地了解细胞内信号传导和细胞复制的相互作用的后果。该项目的长期目标是利用这些分子之间的关系来开发新的更有效的治疗方法来治疗这种毁灭性的疾病。虽然本研究的重点是MIF和T4在PAH发病机制中的相互作用，但研究中获得的数据将与MIF升高的其他心肺疾病状态直接相关，包括中风、心血管疾病、心肌梗死、肺纤维化和阻塞性睡眠呼吸暂停。

DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is a chronic progressive disorder that leads to remodeling of blood vessels in the lung, low oxygen in the blood, right-sided heart failure and death. The poor prognosis and lack of effective PAH disease-modifying agents underscore the need for a better understanding of disease pathogenesis in order to identify new therapeutic approaches. This proposal addresses the molecular mechanisms involved in the development and progression of PAH. Specifically, we will examine - at both the physiological and the cellular level - the effects of a previously unrecognized, clinically relevant interaction between a proinflammatory cytokine [Macrophage Migration Inhibitory Factor (MIF)] and a thyroid hormone [Thyroxine (T4)] in PAH. We have identified MIF as a critical mediator in the development and progression of PAH and further, we have made the surprising discovery that T4 is a natural ligand for and inhibitor of MIF's inflammatory activity. We hypothesize that the dramatic increase in circulating MIF observed during the development of PAH alters the normal plasma MIF-free T4 ratio and underlies the high prevalence of hypothyroidism that has been reported in patients with pulmonary hypertension. The modified status of MIF and T4 in the plasma profoundly changes the interactions of these molecules with their respective cellular receptors leading to altered intracellular signaling and vascular cell proliferation. We outline a multi-faceted approach involving clinical studies, animal models and in vitro assessments. We will examine the MIF-T4 relationship in patients with PAH, both during disease progression and before/after a standardized exercise challenge. We will further examine the interrelationship between these molecules in both animal models of pulmonary vascular remodeling and at a cellular level to understand better the consequence of the interaction on intracellular signaling and cell replication. The long term goal of the project is to exploit the relationship between these molecules to develop new and more effective therapeutic approaches for the treatment this devastating disease. While this proposal focuses on the interactions of MIF and T4 in the pathogenesis of PAH, data achieved in the study will be directly relevant to other cardiopulmonary disease states in which MIF is increased including stroke, cardiovascular disease, myocardial infarction, pulmonary fibrosis and obstructive sleep apnea.