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

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.