Leukocyte adhesion molecules modulate inflammation of cartilage in joint trauma

白细胞粘附分子调节关节创伤中软骨炎症

• 批准号: 8058772
• 负责人: Dejan Milentijevic
• 金额: $ 8.32万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058772
• 关键词: Acute; Adherence; Adult; Affect; Age; Arthritis; Aspirate substance; Attenuated; Autologous; Biological Process; Biomechanics; Blocking Antibodies; Blunt Trauma; Cartilage; Cartilage Matrix; Catabolic Process; Cattle; Cell Adhesion Molecules; Cell Death; Cell Survival; Cells; Cessation of life; Chondrocytes; Clinical; Coculture Techniques; Degenerative polyarthritis; Development; Dinoprostone; Enzymes; Etiology; Event; Extracellular Matrix; Functional disorder; Hemarthrosis; Histology; Hour; ITGB2 gene; Incubated; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Joints; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Ligands; Lymphocyte; Matrix Metalloproteinases; Mechanics; Modality; Modeling; Monitor; Pain; Pathogenesis; Patients; Phase; Play; Property; Quality of life; Reporting; Role; Sampling; Severities; Signal Transduction; Site; Swelling; Syndrome; TNF gene; Testing; Tissues; Trauma; Traumatic Arthropathy; aggrecanase; arthropathies; articular cartilage; autocrine; cytokine; effusion; improved; injured; insight; joint injury; leukocyte activation; middle age; monocyte; neutrophil; osteochondral tissue; paracrine; peripheral blood; public health relevance; research study; response

DESCRIPTION (provided by applicant): Blunt trauma to a joint is commonly associated with swelling, hemarthrosis and pain as result of injury to the surrounding tissues. Influx of leukocytes into the joint can cause a secondary insult to already traumatized articular cartilage which may predispose the joint to develop post-traumatic arthritis. My preliminary studies found that when autologous leukocytes were co-cultured with traumatized cartilage they caused more matrix damage and cell death. My main hypothesis is that mechanical trauma to the articular cartilage will expose matrix attachment sites for leukocytes to adhere to the matrix, and also expose chondrocyte ligands, both of which will result in the leukocytes and chondrocytes excreting inflammatory cytokines to further degrade the cartilage. I will use a bovine explant model to characterize how the severity of the mechanical trauma to the cartilage modulates the degree of the inflammatory response. I will also identify specific adhesion molecules on leukocytes (neutrophils, monocytes and lymphocytes) that facilitate interaction with traumatized articular cartilage to cause the inflammatory response in the tissue. To test these hypotheses I will apply different levels of trauma to cartilage and incubate cartilage with autologous peripheral blood leukocyte subpopulations with and without the presence of blocking antibodies for adhesion molecules (CD18, CD29 and Lselectin). These experiments will be performed at the cellular level by monitoring cell viability, inflammatory cytokines (IL-1, TNF-a, NO, PGE2) and matrix enzymes (MMP, aggrecanase, matrix loss), and at the structural level by analyzing the extracellular matrix (biomechanical properties properties, histology). The etiology of post-traumatic osteoarthritis is not completely known. It is a joint disease that affects all ages, particularly young and middle-aged adults. Joint trauma and articular cartilage survival remains a very serious clinical problem. Proposed study will give us a better understanding of the association between inflammatory events and the biological processes occurring in the joint after blunt trauma. PUBLIC HEALTH RELEVANCE: Project Narrative Joint arthritis can occur as a result of a joint injury. Why the articular cartilage with our joints wakens down as a result of the trauma is not well understood. Post-traumatic arthritis is a syndrome of joint degeneration and dysfunction that affects all ages, particularly young and middle-aged adults. Of the foremost importance is to first understand the mechanisms how acute inflammation can predispose joint to develop post-traumatic arthritis which will be essential for the improving the quality of life for patients by developing treatment modalities.

描述(由申请人提供)： 关节的钝性创伤通常与周围组织损伤引起的肿胀、关节出血和疼痛有关。白细胞涌入关节可能会对已经受损的关节软骨造成二次伤害，这可能会使关节容易患上创伤后关节炎。我的初步研究发现，当自体白细胞与创伤软骨共培养时，它们会导致更多的基质损伤和细胞死亡。我的主要假设是，关节软骨的机械性损伤会暴露出白细胞附着在基质上的基质附着部位，也暴露出软骨细胞的配体，这两者都会导致白细胞和软骨细胞分泌炎性细胞因子，进一步降解软骨。我将使用牛外植体模型来描述软骨机械损伤的严重程度如何调节炎症反应的程度。我还将确定白细胞(中性粒细胞、单核细胞和淋巴细胞)上的特定黏附分子，这些黏附分子有助于与创伤关节软骨相互作用，导致组织中的炎症反应。为了验证这些假设，我将对软骨施加不同程度的创伤，并将软骨与自体外周血白细胞亚群孵育，其中存在和不存在针对黏附分子(CD18、CD29和L选择素)的封闭抗体。这些实验将在细胞水平上通过监测细胞活力、炎症细胞因子(IL-1、肿瘤坏死因子-α、一氧化氮、前列腺素E_2)和基质酶(基质金属蛋白酶、聚集酶、基质丢失)来进行，并在结构水平上通过分析细胞外基质(生物力学特性、组织学)来进行。创伤后骨关节炎的病因尚不完全清楚。这是一种影响所有年龄段的关节疾病，特别是年轻人和中年人。关节创伤和关节软骨存活仍然是一个非常严重的临床问题。拟议的研究将使我们更好地了解炎症事件与钝性创伤后关节发生的生物过程之间的联系。 公共卫生相关性： 项目简介关节损伤可能会导致关节关节炎。为什么我们关节的关节软骨会因为创伤而苏醒，这还不是很清楚。创伤后关节炎是一种关节退行性变和功能障碍的综合征，影响所有年龄段的人，特别是年轻人和中年人。最重要的是首先了解急性炎症如何使关节易患创伤后关节炎的机制，这对于通过开发治疗方法来改善患者的生活质量至关重要。