Leukocyte adhesion molecules modulate inflammation of cartilage in joint trauma

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、关节积血和疼痛有关。白细胞流入关节会对已经创伤的关节软骨造成二次损伤，这可能使关节易于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同培养时，它们会导致更多的基质损伤和细胞死亡。我的主要假设是，关节软骨的机械创伤将暴露白细胞粘附于基质的基质附着位点，并且也暴露软骨细胞配体，这两者都将导致白细胞和软骨细胞分泌炎性细胞因子以进一步降解软骨。我将使用牛移植模型来描述机械创伤对软骨的严重程度如何调节炎症反应的程度。我还将鉴定白细胞（中性粒细胞、单核细胞和淋巴细胞）上的特异性粘附分子，这些粘附分子促进与创伤关节软骨的相互作用，从而引起组织中的炎症反应。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，其中存在和不存在粘附分子（CD 18，CD 29和L选择素）的阻断抗体。这些实验将在细胞水平上通过监测细胞活力、炎性细胞因子（IL-1、TNF-α、NO、PGE 2）和基质酶（MMP、聚集蛋白聚糖酶、基质损失）进行，并在结构水平上通过分析细胞外基质（生物力学性质、组织学）进行。创伤后骨关节炎的病因尚不完全清楚。它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钝性创伤后关节中发生的炎症事件和生物学过程之间的关联。 公共卫生相关性： 关节炎是一种常见的关节炎，是由关节炎引起的。为什么我们的关节软骨会因为创伤而醒来，还没有很好的理解。创伤后关节炎是一种关节退化和功能障碍综合征，影响所有年龄段，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模式来改善患者的生活质量至关重要。

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.