NSAIDs and the Role of COX2 in Biologic Scaffold-Mediated Tissue Reconstruction

NSAIDs 和 COX2 在生物支架介导的组织重建中的作用

• 批准号: 8823859
• 负责人: Christopher L Dearth
• 金额: $ 7.79万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823859
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Biochemistry; Biocompatible Materials; Biological; Bladder; Caring; Cell physiology; Clinic; Clinical Data; Coxibs; Cyclooxygenase Inhibitors; Dermis; Development; Dinoprost; Dinoprostone; Dose; Drug usage; Event; Extracellular Matrix; FDA approved; Fibrosis; Hernia; Immune response; Implant; In Vitro; Inflammation; Inflammatory; Injury; Institutes; Integrins; Knowledge; Ligaments; Link; Mediating; Medicine; Modeling; Molecular; Molecular Biology; Molecular Profiling; Molecular Target; Muscle; Myocardium; Organ; Outcome; PTGS1 gene; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Plastics; Play; Population; Postoperative Period; Process; Production; Psychological reinforcement; Regenerative Medicine; Regenerative response; Reporting; Research Personnel; Role; Rotator Cuff; Signal Transduction; Site; Skeletal Muscle; Skeletal muscle injury; Small Intestines; Submucosa; System; Technology; Tendon structure; Tissue Engineering; Tissues; Treatment Protocols; Up-Regulation; Variant; Work; base; celecoxib; clinically relevant; cohort; collaborative environment; cyclooxygenase 2; design; implantation; improved; in vivo; inhibitor/antagonist; injured; injury and repair; macrophage; muscle regeneration; myogenesis; next generation; novel; programs; public health relevance; receptor; repaired; response; response to injury; scaffold; tissue reconstruction; tissue repair

DESCRIPTION (provided by applicant): NSAIDS and the Role of COX2 in Biologic Scaffold-Mediated Tissue Reconstruction Extracellular matrix based biologic scaffolds are utilized extensively to improve the host response to injury by shifting the response away from an inflammatory, fibrotic response and towards a regenerative response. A wide variety of biologic scaffolds are used clinically for the repair and reinforcement of numerous tissues and organs. Despite a large cohort of clinical data showing beneficial results, occasionally these biologic scaffold materials fail to induce or only partially induce a beneficial remodeling response. Minimizing this variability requires an intimate knowledge of the molecular and cellular processes that biologic scaffolds initiate during the remodeling process. Unfortunately, to date, the mechanism(s) by which biologic scaffolds promote constructive remodeling are not completely understood. However, modulation of the host innate immune response - and more specifically, macrophages - toward a regulatory and constructive phenotype has been shown to be critically important. Macrophages have been shown to occupy a wide array of interchangeable phenotypes spanning the classic pro-inflammatory phenotype (M1) at one extreme to the regulatory, anti- inflammatory phenotype (M2) at the other. Numerous reports have indicated that biologic scaffolds promote an M2 macrophage phenotype during the tissue remodeling cascade. Strikingly, both the development of an M2 phenotype and the remodeling of injured skeletal muscle are strongly influenced by the soluble factors that are synthesized by Cyclooxygenase 2 (COX2). Given that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are well-characterized, potent inhibitors of COX1 and 2, it is plausible that prescription of NSAIDs after biologic scaffold implantation could alter the endogenous constructive tissue remodeling process. The central theme of this proposal is that COX2 up regulation is a critical component of the biologic scaffold initiated tissue remodeling program and administration of NSAIDs may alter the overall tissue remodeling outcome. Aim 1 seeks to establish a firm mechanistic link between biologic scaffold stimulated COX2 up regulation in macrophages and its effect on myogenesis using a well-established in vitro system. This system will then be utilized to determine the effect(s) of NSAIDs on both the macrophage phenotype and the myogenic response. Aim 2 furthers these studies by investigating macrophage phenotype, myogenesis, and COX2 expression in a well-established muscle injury model. This model will then be utilized with NSAID treatments to determine the effect of NSAIDs on the remodeling outcome. The completion of these studies will greatly enhance our understanding of the molecular events that biologic scaffolds trigger to initiate a constructive tissue remodeling response, and if NSAIDs alter those events and the remodeling outcome. Together these studies may provide a new metric for the design of next generation biologic scaffolds as well as provide useful information to physicians utilizing regenerative medicine technologies who may be prescribing NSAIDs for post-operative care.

描述（由申请人提供）：NSAIDS和COX2在生物支架介导的组织重建基于细胞外基质基质外基质基质中的作用被广泛利用，以通过将炎症，纤维化反应和对更新的反应转移到损伤中来改善宿主对损伤的反应。在临床上使用多种生物支架来修复和增强许多组织和器官。尽管有大量临床数据显示出有益结果，但有时这些生物支架材料无法诱导或仅部分诱导有益的重塑反应。最小化这种可变性需要对生物支架在重塑过程中启动的分子和细胞过程有深入的了解。不幸的是，迄今为止，尚不完全了解生物支架促进建设性重塑的机制。但是，对宿主先天免疫反应的调节（更具体地说是巨噬细胞）对调节性和建设性表型的调节至关重要。巨噬细胞已被证明占据了各种可互换的表型，这些表型跨越了经典的促炎表型（M1），这是一个极端的一个极端，而另一个是抗炎症表型（M2）。许多报道表明，生物支架在组织重塑级联过程中促进了M2巨噬细胞表型。令人惊讶的是，M2表型的发展和受伤的骨骼肌的重塑都受到环氧酶2（Cox2）合成的可溶因子的强烈影响。鉴于非甾体类抗炎药（NSAIDS）是特征良好的COX1和2的有效抑制剂，因此，在生物支架植入后的NSAID处方可以改变内源性建设性的结构性组织重塑过程。 该提案的主要主题是COX2 UP调节是生物支架引发的组织重塑程序的关键组成部分，而NSAID的给药可能会改变整体组织重塑结果。 AIM 1试图在巨噬细胞中刺激的COX2刺激COX2之间建立牢固的机械联系，并使用良好的体外系统对巨噬细胞的调节及其对肌发生的影响。然后，将利用该系统来确定NSAID对巨噬细胞表型和肌源性反应的影响。目标2通过研究良好的肌肉损伤模型中的巨噬细胞表型，肌发生和COX2表达来进一步进一步。然后，该模型将通过NSAID处理来确定NSAID对重塑结果的影响。这些研究的完成将大大增强我们对生物支架触发的分子事件的理解，以引发建设性组织重塑反应，如果NSAIDS改变了这些事件和重塑结果。这些研究共同为下一代生物脚手架设计提供了新的指标，并为利用可再生医学技术的医生提供了有用的信息，这些技术可能正在开处方NSAID进行术后护理。