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

Treg 和 IL-35 调节左室衰竭所致肺重塑和右心肥厚的机制

• 批准号: 10116063
• 负责人: YINGJIE CHEN
• 金额: $ 54.82万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116063
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Apoptosis; Attenuated; B-Lymphocytes; Cardiac; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Congestive Heart Failure; Dendritic cell activation; Development; Disease; Dyspnea; Exhibits; Failure; Fibrosis; Genes; Goals; Heart; Heart Hypertrophy; Heart failure; Human Herpesvirus 4; IL2 gene; IL2RA gene; Immune Tolerance; Immunosuppression; Infiltration; Inflammation; Interleukin-1 beta; Interleukin-2; Interleukins; Left; Left Ventricular Dysfunction; Left ventricular structure; Leukocytes; Liver; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Memory; Monoclonal Antibodies; Mus; Myocardial Infarction; Myocarditis; Patients; Pilot Projects; Play; Process; Production; Pulmonary Hypertension; Regulatory T-Lymphocyte; Right Ventricular Hypertrophy; Role; Secondary to; Solid; Stroke; Structure of parenchyma of lung; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Tissues; Ventricular; cardiovascular risk factor; cytokine; heart damage; improved; inhibitor/antagonist; innovation; insight; interest; lung injury; neutralizing antibody; novel; stem

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.

项目摘要 该项目的主要目标是研究T调节细胞（Treg）和白介素的机制 35（IL-35）在减弱肺注射和重塑时导致谁型2型肺动脉高压 （pH），并阻止左心室（LV）无法右心（RV）的过渡过程 肥大和失败。虽然大多数在慢性心力衰竭（CHF）领域的研究都集中在左心室，但我们 最近证明，LV衰竭会导致严重的肺部感染，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，以至于肺组织与肝脏一样固体 CHF动物中的组织。现在，我们已经获得了可靠的证据，表明Treg有效抑制LV 衰竭引起的肺注射和现有LV衰竭的动物中的2型pH值，但是机制 仍然未知。 IL-35是由IL-12α（p35）和爱泼斯坦 - 巴尔病毒诱导的基因-3组成的异二聚体 （EBI3）亚基。 IL-35可以有效地促进Treg和调节B细胞（Bregs）的形成。 因此，IL-35可能在减弱肺注射/重塑，2型pH和 从LV失败到RV肥大和通过Treg依赖或Treg无关的失败 机制。在这里，我们将调查Tregs和IL-35如何影响CHF诱导的肺注射和类型 2 ph。特定的AIM-1将主要确定抑制肺的Tregs和IL-35的机制 炎症，2型pH和现有LV衰竭的小鼠的LV失败到RV衰竭的过渡。我们 将执行以下研究：（i）检查Treg耗竭对IL-35生产，T细胞和 树突状细胞激活，肺注射，2型pH和从LV失败到RV肥大的过渡 （ii）确定为什么Treg与T效应记忆细胞的比率大大降低 在CHF动物的肺组织中，是否可以通过Treg增殖的改变或 凋亡，（iii）确定IL-35在抑制肺重塑和2型pH中的机制 现有的LV失效，重点是Treg和T细胞激活。特定的AIM-2将决定串扰 在Tregs和IL-35之间，及其在调节肺注射和2型pH中的相应作用 与现有的LV故障。我们将进行以下研究：（i）确定最佳的IL-35是否需要IL-35 通过Treg诱导抑制肺注射，2型pH和从LV失败到的过渡 RV肥大/失败。 （ii）确定IL-35非依赖性Treg在衰减肺注射中的作用， 2型pH和CHF进展，（iii）确定IL-35的给药是否足以营救 TREG耗竭诱导的肺注射和现有LV衰竭的小鼠的型2型pH值。成功的 该项目的完成将为心血管保护机制提供令人兴奋而新颖的见解 Tregs和IL-35，并证明靶向Treg和IL-35的治疗潜力 肺部炎症，以及从LV失败到RV肥大和/或失败的过渡。