title: The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells.
abstract: Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist even after LA removal.
authors: Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors: Andrea
authors: A
authors: Gray
authors: Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors: Ileana
authors: I
authors: Marrero-Berrios
authors: Department of Anesthesiology, New York Methodist Hospital, Brooklyn, NY, USA.
authors: Jonathan
authors: J
authors: Weinberg
authors: Department of Anesthesiology, New York Methodist Hospital, Brooklyn, NY, USA.
authors: Devasena
authors: D
authors: Manchikalapati
authors: Department of Anesthesiology, New York Methodist Hospital, Brooklyn, NY, USA.
authors: Joseph
authors: J
authors: SchianodiCola
authors: Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. Electronic address: schloss@soemail.rutgers.edu.
authors: Rene S
authors: RS
authors: Schloss
authors: Department of Anesthesiology, New York Methodist Hospital, Brooklyn, NY, USA.
authors: Joel
authors: J
authors: Yarmush
mesh_terms: D000779:Anesthetics, Local / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002045:Bupivacaine / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D008012:Lidocaine / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D008012:Lidocaine; D015232:Dinoprostone; D002045:Bupivacaine
keywords: Inflammation; Local anesthetics; Macrophages; Mesenchymal stromal cells