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: 7866577
• 负责人: Dejan Milentijevic
• 金额: $ 8.66万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866577
• 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; 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）： 关节钝挫伤通常与周围组织损伤导致的肿胀、关节积血和疼痛有关。白细胞流入关节会对已经受伤的关节软骨造成二次损伤，这可能使关节容易发展为创伤后关节炎。我的初步研究发现，当自体白细胞与创伤软骨共培养时，它们会引起更多的基质损伤和细胞死亡。我的主要假设是，关节软骨的机械创伤会暴露白细胞粘附基质的基质附着位点，也会暴露软骨细胞配体，这两者都会导致白细胞和软骨细胞分泌炎症细胞因子，进一步降解软骨。我将使用牛外植体模型来表征软骨机械创伤的严重程度如何调节炎症反应的程度。我还将识别白细胞（中性粒细胞、单核细胞和淋巴细胞）上的特定粘附分子，这些分子有助于与受伤的关节软骨相互作用，从而引起组织中的炎症反应。为了测试这些假设，我将对软骨施加不同程度的创伤，并在存在或不存在粘附分子（CD18、CD29 和 Lselectin）阻断抗体的情况下，将软骨与自体外周血白细胞亚群一起孵育。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、TNF-a、NO、PGE2）和基质酶（MMP、蛋白聚糖酶、基质损失）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）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，特别是青壮年的关节疾病。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中发生的生物过程之间的关联。 公共卫生相关性： 项目叙述 关节损伤可能导致关节关节炎。为什么我们关节的关节软骨会因创伤而苏醒，目前尚不清楚。创伤后关节炎是一种关节退化和功能障碍的综合征，影响所有年龄段，尤其是青壮年。最重要的是首先了解急性炎症如何促使关节发展为创伤后关节炎的机制，这对于通过开发治疗方式来改善患者的生活质量至关重要。