Mechanisms of Treg and IL-35 in Regulating LV Failure-induced Lung Remodeling and Right Heart Hypertrophy

项目摘要 本课题的主要目的是研究调节性T细胞（Tlymphocytes，Tlymphocytes）和白细胞介素（IL-2）的作用机制。 35（IL-35）在减轻导致WHO 2型肺动脉高压的肺部炎症和重塑中的作用 (PH)阻止左心室衰竭向右心室衰竭的过渡过程 肥大和衰竭。虽然大多数慢性心力衰竭（CHF）领域的研究集中在左心室，但我们 最近证实LV衰竭导致严重的肺部炎症、纤维化和严重的2型PH。 值得注意的是，在某些情况下，肺重塑是如此广泛，以至于肺组织变得像肝脏一样坚固 CHF动物中的组织。我们现在已经获得了确凿的证据，表明TdR能有效抑制LV 衰竭诱导的肺部炎症，以及存在LV衰竭的动物中的2型PH，但机制 仍然未知。IL-35是由IL-12α（p35）和EB病毒诱导基因3（Epstein-Barr virus induced gene-3）组成的异源二聚体 （EBI 3）亚基。IL-35可有效促进TcB和调节性B细胞（BcB）的形成。 因此，IL-35可能在减轻肺炎症/重塑、2型PH和肺内炎症/重塑中起重要作用。 从LV衰竭转变为RV肥大和通过Treg依赖性或Treg非依赖性的衰竭 机制等在这里，我们将研究THP和IL-35如何影响CHF诱导的肺部炎症，以及 2 PH.特异性Aim-1将主要决定TNF和IL-35抑制肺功能的机制 炎症，2型PH，以及在存在LV衰竭的小鼠中从LV衰竭向RV衰竭的转变。我们 将进行以下研究：（i）检查Treg耗竭对IL-35产生、T细胞和T淋巴细胞的影响。 树突状细胞活化、肺部炎症、2型PH和从LV衰竭向RV肥大的转变 和/或失败，（ii）确定为什么TcB与T效应记忆细胞的比率显著降低 在CHF动物的肺组织中，以及这是否可以通过Treg增殖或 细胞凋亡，和（iii）确定IL-35抑制小鼠肺重塑和2型PH的机制 与现有的左心室衰竭，重点是T细胞活化和T细胞活化。具体目标-2将确定串扰 探讨了TGFAP与IL-35在小鼠肺炎症和2型PH中的相互作用 左心室衰竭我们将进行以下研究：（i）确定IL-35是否是最佳治疗所必需的。 Treg诱导在减轻肺部炎症、2型PH和从LV衰竭向 RV肥大/衰竭。(ii)确定IL-35-非依赖性TGFAP在减轻肺部炎症中的作用， 2型PH和CHF进展，和（iii）确定IL-35的施用是否足以挽救 Treg耗竭诱导的LV衰竭小鼠的肺部炎症和2型PH成功 本项目的完成将为心血管保护机制提供令人兴奋和新颖的见解。 的TcR和IL-35的表达，并证明靶向TcR和IL-35的治疗潜力，以停止或逆转 肺部炎症，以及从LV衰竭向RV肥大和/或衰竭的转变。

PROJECT SUMMARY The central goal of this project is to investigate the mechanisms of T regulatory cells (Tregs) and interleukin 35 (IL-35) in attenuating lung inflammation and remodeling leading to WHO type-2 pulmonary hypertension (PH), and arresting the transitional process from left ventricular (LV) failure to right ventricular (RV) hypertrophy and failure. While most studies in the chronic heart failure (CHF) field focus on left ventricle, we recently demonstrated that LV failure causes profound lung inflammation, fibrosis, and severe type-2 PH. Remarkably, in some cases lung remodeling is so extensive that the lung tissue becomes as solid as liver tissue in CHF animals. We have now obtained solid evidence that Tregs are effective in suppressing LV failure-induced lung inflammation, and type-2 PH in animals with existing LV failure, but the mechanisms remain unknown. IL-35 is a heterodimer composed of IL-12α (p35) and Epstein-Barr virus-induced gene-3 (EBI3) subunits. IL-35 can effectively promote the formation of Tregs and regulatory B cells (Bregs). Therefore, IL-35 may play an important role in attenuating lung inflammation/remodeling, type-2 PH, and the transition from LV failure to RV hypertrophy and failure through both Treg-dependent or Treg-independent mechanisms. Here we will investigate how Tregs and IL-35 affect CHF-induced lung inflammation, and type- 2 PH. Specific Aim-1 will mainly determine the mechanisms of Tregs and IL-35 in suppressing lung inflammation, type-2 PH, and the transition from LV failure to RV failure in mice with existing LV failure. We will perform the following studies: (i) examine the impact of Treg depletion on IL-35 production, T cell and dendritic cell activation, lung inflammation, type-2 PH, and the transition from LV failure to RV hypertrophy and/or failure in mice, (ii) determine why the ratio of Tregs to T effector memory cells is dramatically reduced in lung tissue in CHF animals, and whether this can be explained by alterations in Treg proliferation or apoptosis, and (iii) determine the mechanism of IL-35 in suppressing lung remodeling and type-2 PH in mice with existing LV failure with a focus on Tregs and T cell activation. Specific Aim-2 will determine the crosstalk between Tregs and IL-35, and their corresponding roles in regulating lung inflammation and type-2 PH in mice with existing LV failure. We will perform following studies: (i) Determine if IL-35 is required for the optimal protection by Treg induction in attenuating lung inflammation, type-2 PH, and the transition from LV failure to RV hypertrophy/failure. (ii) determine the role of IL-35-independent Tregs in attenuating lung inflammation, type-2 PH and CHF progression, and (iii) determine whether administration of IL-35 is sufficient to rescue Treg depletion-induced lung inflammation and type-2 PH in mice with existing LV failure. Successful completion of this project will provide exciting and novel insights into cardiovascular protective mechanism(s) of Tregs and IL-35, and demonstrate the therapeutic potential of targeting Tregs and IL-35 to halt or reverse lung inflammation, and the transition from LV failure to RV hypertrophy and/or failure.