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

描述(申请人提供)：非甾体抗炎药和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改善宿主对损伤的反应，方法是将反应从炎症、纤维化反应转向再生反应。各种各样的生物支架被用于临床修复和加固大量的组织和器官。尽管大量的临床数据显示了有益的结果，但这些生物支架材料有时无法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对生物支架在重建过程中启动的分子和细胞过程有深入的了解。遗憾的是，到目前为止，生物支架促进建设性重塑的机制(S)还不完全清楚。然而，宿主的先天性免疫反应--更具体地说，巨噬细胞--向调节性和建设性表型的调节被证明是至关重要的。巨噬细胞被证明占据了广泛的可互换的表型，从经典的促炎性表型(M1)到调节性、抗炎性表型(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。值得注意的是，M2表型的发展和受损骨骼肌的重塑都受到环氧合酶2(COX2)合成的可溶性因子的强烈影响。鉴于非类固醇抗炎药(NSAIDs)是COX1和COX2的有效抑制剂，在生物支架植入后处方NSAIDs可能会改变内源性建设性组织重塑过程。这一建议的中心主题是COX2上调是生物支架启动的组织重塑计划的关键组成部分，而非类固醇抗炎药的应用可能会改变整体组织重塑的结果。目的1利用成熟的体外系统，试图建立生物支架刺激巨噬细胞中COX2上调与其对肌肉形成的影响之间的确切机制联系。然后将利用该系统来确定非类固醇抗炎药对巨噬细胞表型和肌源性反应的影响(S)。目的2通过在已建立的肌肉损伤模型中研究巨噬细胞表型、肌肉生成和COX2的表达来进一步研究这些研究。然后，该模型将与非类固醇抗炎药联合使用，以确定非类固醇抗炎药对重塑结果的影响。这些研究的完成将极大地提高我们对生物支架触发的分子事件启动建设性组织重塑反应的理解，以及非类固醇抗炎药是否改变这些事件和重塑结果。总之，这些研究可能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，这些医生可能会开出非甾体抗炎药用于术后护理。

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.