title: Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts.
abstract: The aged are at increased risk of postoperative wound healing complications. Because local anesthetics are infiltrated commonly into the dermis of surgical wounds, we sought to determine whether local anesthetics adversely affect proliferative and biosynthetic functions of dermal fibroblasts. We also evaluated the effect of local anesthetics on insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1), growth factors that are important regulators of wound healing.
  
  
  
  Human dermal fibroblasts (HFB) from aged and young donors were exposed to local anesthetic agents at clinically relevant concentrations. We screened the effects of lidocaine, bupivacaine, mepivacaine, and ropivacaine on proliferation of HFB. Lidocaine was most detrimental to proliferation in HFB. We then evaluated the effect of lidocaine on expression and function of the growth factors, IGF-1 and TGF-β1. Lastly, concurrent exposure to lidocaine and IGF-1 or TGF-β1 was evaluated for their effects on proliferation and expression of dermal collagens, respectively.
  
  
  
  Lidocaine and mepivacaine inhibited proliferation in aged HFB (for lidocaine 88% of control, 95% confidence interval [CI], 80%-98%, P = .009 and for mepivacaine 90% of control, 95% CI, 81%-99%, P = .032) but not in young HFB. Ropivacaine and bupivacaine did not inhibit proliferation. Because of the clinical utility of lidocaine relative to mepivacaine, we focused on lidocaine. Lidocaine decreased proliferation in aged HFB, which was abrogated by IGF-1. Lidocaine inhibited transcripts for IGF-1 and insulin-like growth factor-1 receptor (IGF1R) in fibroblasts from aged donors (IGF-1, log2 fold-change -1.25 [42% of control, 95% CI, 19%-92%, P = .035] and IGF1R, log2 fold-change -1.00 [50% of control, 95% CI, 31%-81%, P = .014]). In contrast, lidocaine did not affect the expression of IGF-1 or IGF1R transcripts in the young HFB. Transcripts for collagen III were decreased after lidocaine exposure in aged and young HFB (log2 fold-change -1.28 [41% of control, 95% CI, 20%-83%, P = .022] in aged HFB and log2 fold-change -1.60 [33% of control, 95% CI, 15%-73%, P = .019] in young HFB). Transcripts for collagen I were decreased in aged HFB (log2 fold-change -1.82 [28% of control, 95% CI, 14%-58%, P = .006]) but not in the young HFB. Similar to the transcripts, lidocaine also inhibited the protein expression of collagen III in young and aged HFB (log2 fold-change -1.79 [29% of control, 95% CI, 18%-47%, P = .003] in young HFB and log2 fold-change -1.76 [30% of control, 95% CI, 9%-93%, P = .043] in aged HFB). The effect of lidocaine on the expression of collagen III protein was obviated by TGF-β1 in both young and aged HFB.
  
  
  
  Our results show that lidocaine inhibits processes relevant to dermal repair in aged HFB. The detrimental responses to lidocaine are due, in part, to interactions with IGF-1 and TGF-β1.
authors.affiliation: From the *Department of Anesthesiology and Pain Medicine and †Division of Gerontology and Geriatric Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington; and ‡Center for Biomedical Statistics, Institute for Translational Health Sciences, University of Washington, Seattle, Washington.
authors.forename: Itay
authors.initials: I
authors.lastname: Bentov
authors.forename: Mamatha
authors.initials: M
authors.lastname: Damodarasamy
authors.forename: Charles
authors.initials: C
authors.lastname: Spiekerman
authors.forename: May J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D000779:Anesthetics, Local / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D020405:Dermis / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D008012:Lidocaine / Q000633:toxicity*; D008297:Male; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology
chemical_list: D000779:Anesthetics, Local; D008012:Lidocaine