title: Inhibition of COX1/2 alters the host response and reduces ECM scaffold mediated constructive tissue remodeling in a rodent model of skeletal muscle injury.
abstract: Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a constructive tissue remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the constructive remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration.
  
  
  CONCLUSIONS
  COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the constructive remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated constructive remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered.
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, United States; DoD-VA Extremity Trauma & Amputation Center of Excellence, Walter Reed National Military Medical Center, Bethesda, MD 20889, United States. Electronic address: Christopher.L.Dearth.civ@mail.mil.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Dearth
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Slivka
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Stewart
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Keane
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Tay
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA 15261, United States.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Londono
authors.affiliation: Department of Kinesiology, The University of Toledo, Toledo, OH 43606, United States.
authors.forename: Qingnian
authors.initials: Q
authors.lastname: Goh
authors.affiliation: Department of Kinesiology, The University of Toledo, Toledo, OH 43606, United States.
authors.forename: Francis X
authors.initials: FX
authors.lastname: Pizza
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Badylak
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D001241:Aspirin / Q000737:chemistry; D051940:B7-2 Antigen / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000293:injuries*; D010434:Pepsin A / Q000737:chemistry; D010641:Phenotype; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D044968:Regenerative Medicine / Q000379:methods; D023822:Tissue Engineering / Q000379:methods; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051940:B7-2 Antigen; D016861:Cyclooxygenase Inhibitors; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D011453:Prostaglandins; D011956:Receptors, Cell Surface; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D010434:Pepsin A; D001241:Aspirin
keywords: Biologic scaffold; Extracellular matrix; Extremity Trauma; Host response; Macrophage polarization; Regenerative medicine; Skeletal muscle injury