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中的作用基于细胞外基质的生物支架被广泛用于通过将反应从炎症、纤维化反应转向再生来改善宿主对损伤的反应回复。临床上使用多种生物支架来修复和加固众多组织和器官。尽管大量临床数据显示出有益的结果，但有时这些生物支架材料不能诱导或仅部分诱导有益的重塑反应。最大限度地减少这种变异性需要深入了解生物支架在重塑过程中启动的分子和细胞过程。不幸的是，迄今为止，生物支架促进建设性重塑的机制尚不完全清楚。然而，将宿主先天免疫反应（更具体地说是巨噬细胞）调节至调节性和建设性表型已被证明至关重要。巨噬细胞已被证明具有多种可互换的表型，从一个极端的经典促炎表型（M1）到另一个极端的调节性抗炎表型（M2）。许多报告表明，生物支架在组织重塑级联过程中促进 M2 巨噬细胞表型。引人注目的是，M2 表型的发育和受损骨骼肌的重塑都受到环加氧酶 2 (COX2) 合成的可溶性因子的强烈影响。鉴于非甾体抗炎药 (NSAID) 是 COX1 和 2 的特征明确、有效的抑制剂，生物支架植入后服用 NSAID 可能会改变内源性建设性组织重塑过程。 该提案的中心主题是 COX2 上调是生物支架启动的组织重塑计划的关键组成部分，并且 NSAID 的施用可能会改变整体组织重塑结果。目标 1 试图利用成熟的体外系统，在生物支架刺激的巨噬细胞中 COX2 上调与其对肌生成的影响之间建立牢固的机制联系。然后，该系统将用于确定非甾体抗炎药对巨噬细胞表型和肌源性反应的影响。目标 2 通过研究成熟的肌肉损伤模型中的巨噬细胞表型、肌生成和 COX2 表达来进一步推进这些研究。然后，该模型将与 NSAID 治疗一起使用，以确定 NSAID 对重塑结果的影响。这些研究的完成将极大地增强我们对生物支架触发的分子事件的理解，从而启动建设性的组织重塑反应，以及非甾体抗炎药是否会改变这些事件和重塑结果。这些研究共同可为下一代生物支架的设计提供新的衡量标准，并为使用再生医学技术的医生提供有用的信息，这些医生可能会开非甾体抗炎药进行术后护理。