Immune injury as a driver for the development of ascending aortic aneurysms and dissections

免疫损伤是升主动脉瘤和夹层发展的驱动因素

• 批准号: 10646241
• 负责人: Zhihua Jiang
• 金额: $ 55.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646241
• 关键词: Abdominal Aortic Aneurysm; Ablation; Acceleration; Acute; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Animal Model; Aorta; Aortic Aneurysm; Aortic Rupture; Autoantigens; B-Lymphocytes; Back; Biological; Blood; C3AR1 gene; CD19 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Complement; Complement 3a; Complement 5a; Coupled; Data; Decision Making; Deposition; Development; Disease; Dissection; Equilibrium; Event; Feedback; Foundations; Future; Genes; Genetic; Growth; Helper-Inducer T-Lymphocyte; Human; IL5 gene; Immune; Immune System Diseases; Immune response; Immunity; Immunology; Immunotherapy; Inflammatory Response; Injury; Interferon Type II; Interferons; Interleukin-12; Intervention; Life; Measures; Medial; Mediator; Mission; Modeling; Modification; Molecular; Mus; Natural History; Pathway interactions; Patients; Phenotype; Regulation; Risk Factors; Role; Rupture; Shapes; Signal Transduction; Smooth Muscle Myocytes; Solid; Specimen; Surrogate Endpoint; T-Lymphocyte; Testing; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; United States; Work; adaptive immunity; arm; ascending aorta; cell mediated immune response; complement system; cytokine; druggable target; eosinophil; human subject; immunoregulation; insight; mouse model; neutrophil; novel; peripheral blood; pharmacologic; polarized cell; prevent; programs; receptor; response; restoration; therapeutic development; transcription factor; translational potential

Abstract Acute aortic dissection, particularly the type A dissection (AAD), is a life-threatening condition. Currently, there are no effective measures to prevent its onset and progression. A major barrier to satisfy these critical, unmet clinical needs is the poor understanding of the mechanisms that drive AAD development. AADs usually occur in aortas suffering progressive aneurysmal degeneration. However, compelling clinical evidence suggests that AADs and aortic aneurysms precede through distinct biological pathways. Yet, uncoupling these pathways has been a challenging task due to the silent onset of aortic dissections in patients coupled with a lack of animal models capable of mimicking the development of AAD reliably. To address this issue, we created two novel mouse AAD models, termed as “aortic tear model” and “aortic rupture model”, respectively. The “aortic tear model” develops spontaneous aortic tears with few ruptures in mildly dilated ascending aortas, whereas the “aortic rupture model” features acute aortic dissections with a high rate (40%) of aortic rupture in the first week. Using these models, we tested the long-standing, but unproved, hypothesis—disorders of immune response promote AAD formation. We found that 1) development of aortic tears is paralleled with an increased CD4+ T- cells and CD19+ B-cells in the AAD tissue as well as in the peripheral blood; 2) Th2 polarization via adoptive transfer of ex vivo expanded Th2 cells or neutralization of the Th1 signature cytokine interferon gamma (INFγ) exaggerates AAD dilation; 3) complement components are upregulated and deposited in the medial layer of AADs; and 4) genetic shifting of T-cell-mediated immune response to a Th2 prominent immunity dramatically provokes aortic rupture (>90% in four weeks). These novel findings led to an overall hypothesis that skewing of the inflammatory response in the aneurysmal aortic wall to type 2 immunity promotes AAD development. In this project, we will use genetic, adoptive cell transfer, and pharmacological approaches to evaluate the role of T- cells, B-cells, and complement system in regulating AAD development, with profile of immune cell subsets and cytokine milieu characterized to understand the cellular and molecular events engaged in promoting AAD formation. Critical findings will be validated for their implication across different mouse models, and more importantly, their relevance to human AAD development. Completion of this project will lay a solid foundation for future studies to develop immunotherapies to prevent AAD formation.

摘要 急性主动脉夹层，特别是A型夹层（AAD），是一种危及生命的疾病。目前 没有有效的措施来预防它的发生和发展。一个主要的障碍，以满足这些关键的， 临床需求是对驱动AAD发展的机制的理解不足。AAD通常发生在 患有进行性神经系统退化的脊椎动物。然而，令人信服的临床证据表明， AAD和主动脉瘤通过不同的生物学途径发生。然而，将这些途径分开 由于患者的主动脉夹层无症状发作加上缺乏动物， 能够可靠地模仿AAD发展的模型。为了解决这个问题，我们创造了两个新的 小鼠AAD模型，分别称为“主动脉撕裂模型”和“主动脉破裂模型”。主动脉撕裂 “模型”在轻度扩张的升主动脉中出现自发性主动脉撕裂伴少量破裂，而 “主动脉破裂模型”的特点是急性主动脉夹层，在第一周内主动脉破裂的发生率很高（40%）。 使用这些模型，我们测试了长期存在但未经证实的假设-免疫反应紊乱 促进AAD形成。我们发现：1）主动脉撕裂的发展与CD 4 + T细胞的增加有关， AAD组织以及外周血中的Th 2细胞和CD 19 + B细胞; 2）通过过继性免疫应答的Th 2极化 转移离体扩增的Th 2细胞或中和Th 1特征细胞因子干扰素γ（INFγ） 扩大AAD扩张; 3）补体成分上调并沉积在中间层， AAD;以及4）T细胞介导的免疫应答向Th 2显著免疫的遗传转变 引起主动脉破裂（四周内>90%）。这些新的发现导致了一个总体假设， 动脉瘤主动脉壁对2型免疫的炎症反应促进AAD的发展。在这 项目，我们将使用遗传，过继细胞转移和药理学方法来评估T细胞的作用， 细胞、B细胞和补体系统在调节AAD发展中的作用，以及免疫细胞亚群和 细胞因子环境特征，以了解参与促进AAD的细胞和分子事件 阵关键发现将在不同的小鼠模型中得到验证， 重要的是，它们与人类反倾销发展的相关性。该项目的完成将为 未来的研究开发免疫疗法，以防止AAD的形成。

项目成果

Commonly Used Myh11-CreERT2Strain Carries a Y-Linked Functional Wild-Type Tlr7 Allele.

常用的 Myh11-CreERT2 菌株携带 Y 连锁功能野生型 Tlr7 等位基因。

• DOI: 10.1161/atvbaha.122.318919
• 发表时间: 2023
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Li,Jie;Xu,Haiyan;Hung,Alex;Javed,MuhammadJavad;UpchurchJr,GilbertR;Jiang,Zhihua
• 通讯作者: Jiang,Zhihua

Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.

• DOI: 10.1096/fj.202100484r
• 发表时间: 2021-08
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Nicotine Exacerbates TAAD Formation Induced by Smooth Muscle-Specific Deletion of the TGF-β Receptor 2.

• DOI: 10.1155/2021/6880036
• 发表时间: 2021
• 期刊: Journal of immunology research
• 影响因子: 4.1
• 作者: Chun C;Qi X;Wang F;Madrid KB;Saldarriaga LA;Fisch MR;Brantly ML;Upchurch GR Jr;Jiang Z
• 通讯作者: Jiang Z