Impact of the micromechanical environment on inflammation in AAA progression

微机械环境对 AAA 进展中炎症的影响

• 批准号: 8766950
• 负责人: Naomi C Chesler
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766950
• 关键词: Abdominal Aortic Aneurysm; Affect; Aging; Aneurysm; Angiotensin II; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Apolipoprotein E; Apoptotic; Arteries; Behavior; Biological Assay; Biomechanics; Blood Vessels; Breeding; Cause of Death; Cell Culture Techniques; Cells; Collagen; Collagen Fiber; Data; Defect; Deposition; Development; Diagnosis; Disease; Down-Regulation; Elastases; Elastin; Elderly; Environment; Excision; Extracellular Matrix; Fibroblasts; Flow Cytometry; Foundations; Functional disorder; Future; Gel; Heating; Histologic; Human Characteristics; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Infusion procedures; Knowledge; Lipoproteins; Macrophage Colony-Stimulating Factor; Mechanics; Mediating; Modeling; Mouse Strains; Mus; Mutant Strains Mice; Operative Surgical Procedures; Pathologic Processes; Patients; Peptide Hydrolases; Perfusion; Pharmacologic Substance; Play; Population; Property; Risk; Risk Factors; Rupture; Ruptured Aneurysm; Smooth Muscle Myocytes; Source; Testing; Therapeutic; Tissues; Transgenic Mice; United States; Vascular Diseases; Work; age related; base; crosslink; cytokine; cytotoxic; design; disability; drug development; expectation; in vitro testing; in vivo; insight; macrophage; monocyte; mutant; novel; prevent; public health relevance; vascular inflammation

DESCRIPTION (provided by applicant): Aging is the most important yet least understood risk factor for abdominal aortic aneurysm (AAA), a common, progressive vascular disease with high lethality. The vascular extracellular matrix (ECM) changes with aging, characterized by stiffer and less organized collagen fibers. We hypothesize that these age-related ECM changes predispose older arteries to aneurysm not only by altering vessel mechanical properties but also by influencing the functions of infiltrating inflammatory cells. In this R21, we propose to specifically test how age-related collagen changes affect the inflammatory response during the course of aneurysm development using the transgenic mouse strain Col1a1. The homozygous mutant animals (Col1a1R/R) have been shown to display excessive collagen accumulation and subsequent ECM stiffening as well as exacerbated aneurysm formation. Two Specific Aims are proposed. In Aim 1, we will test whether ECM stiffening accelerates AAA progression and intensifies vascular inflammation by subjecting Col1a1 mutant and wildtype (Col1a1+/+) mice to AAA induction via intraluminal perfusion with elastase (AAA) or heat-inactivated elastase (sham). This so called elastase model is widely accepted for its duplication of major pathological characteristics of human AAAs. We will focus on macrophage-mediated inflammation because macrophages are the predominant type of inflammatory cells found in aneurysmal aorta and are thought to be the major source of elastin degrading proteases. In addition to macrophage recruitment, we will examine macrophage differentiation with the expectation that ECM stiffening facilitates differentiation of the proinflammatory subtype or M1 macrophages or/and suppresses differentiation of the anti-inflammatory subtype or M2 macrophages. Currently, how macrophage subtypes are distributed in aneurysmal tissue and how subtype differentiation may be affected by aging ECM is completely unknown. In Aim 2, we propose culture monocytes (the precursors of macrophages) from wildtype or mutant mice in collagen gels of increasing stiffness to study how collagen-mediated ECM stiffening influences the recruitment and differentiation of inflammatory cells. The results obtained from this study will provide a new concept in understanding aging-associated AAA formation and lay a foundation for future mechanistic studies and drug development. Therefore, our work is significant, novel, and translational.

描述（由申请人提供）：老化是腹主动脉瘤（AAA）最重要但了解最少的风险因素，AAA是一种常见的进行性血管疾病，具有高致死性。血管细胞外基质（ECM）随着年龄的增长而变化，其特征是胶原纤维变硬和组织化程度降低。我们假设这些与年龄相关的ECM变化不仅通过改变血管的机械性能，而且通过影响浸润性炎症细胞的功能，使老年动脉易于发生动脉瘤。在这个R21中，我们建议使用转基因小鼠品系Col 1a 1专门测试年龄相关的胶原蛋白变化如何影响动脉瘤发展过程中的炎症反应。纯合突变动物（Col 1a 1 R/R）显示过度胶原积聚和随后ECM硬化以及动脉瘤形成加剧。提出了两个具体目标。在目标1中，我们将通过用弹性蛋白酶（AAA）或热灭活弹性蛋白酶（sham）腔内灌注对Col 1a 1突变型和野生型（Col 1a 1 +/+）小鼠进行AAA诱导来测试ECM硬化是否加速AAA进展并加剧血管炎症。这种所谓的弹性蛋白酶模型因其复制了人AAA的主要病理特征而被广泛接受。我们将重点关注巨噬细胞介导的炎症，因为巨噬细胞是在动脉瘤主动脉中发现的主要类型的炎性细胞，并且被认为是弹性蛋白降解蛋白酶的主要来源。除了巨噬细胞募集，我们将检查巨噬细胞分化，期望ECM硬化促进促炎亚型或M1巨噬细胞的分化或/和抑制抗炎亚型或M2巨噬细胞的分化。目前，巨噬细胞亚型如何分布在囊性组织中以及亚型分化如何受到老化ECM的影响是完全未知的。在目标2中，我们提出在硬度增加的胶原凝胶中培养野生型或突变型小鼠的单核细胞（巨噬细胞的前体），以研究胶原介导的ECM硬化如何影响炎症细胞的募集和分化。本研究结果为认识老年性腹主动脉瘤的形成机制提供了新的思路，并为今后的机制研究和药物开发奠定了基础。因此，我们的工作是有意义的，新颖的，和翻译。