Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts

Abstract

Background The aged are at increased risk of postoperative wound healing complications. Since local anesthetics are commonly infiltrated into the dermis of surgical wounds, we sought to determine if local anesthetics adversely affect proliferative and biosynthetic functions of dermal fibroblasts. We also evaluated the effect of local anesthetics on IGF-1 and TGF-ß1, growth factors that are important regulators of wound healing. Methods Human dermal fibroblasts from aged and young donors (HFB) 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 the 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-ß1. Lastly, concurrent exposure to lidocaine and IGF-1 or TGF-ß1 were evaluated for their effects on proliferation and expression of dermal collagens, respectively. Results Lidocaine and mepivacaine inhibited proliferation in aged HFB (for lidocaine 88% of control, 95%CI 80%-98%, p=0.009 and for mepivacaine 90% of control, 95%CI 81%-99%, p=0.032), but not in young HFB. Ropivicaine and bupivicaine did not inhibit proliferation. Due to the clinical utility of lidocaine relative to mepivicaine, we focused on lidocaine. Lidocaine decreased proliferation in aged HFB, which was abrogated by IGF-1. Lidocaine inhibited transcripts for IGF-1 and IGF1R in fibroblasts from aged donors (IGF-1, log2 fold-change −1.25 {42% of control, 95%CI 19%-92%, p=0.035} and IGF1R, log2 fold-change of −1.00 {50% of control, 95%CI 31%-81%, p=0.014}). In contrast, lidocaine did not effect 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=0.022} in aged HFB and log2 fold-change −1.60 {33% of control, 95%CI 15%-73%, p=0.019} 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=0.006}), but were 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=0.003} in young HFB and log2 fold-change −1.76 {30% of control, 95%CI 9%-93%, p=0.043} in aged HFB). The effect of lidocaine on expression of collagen III protein was obviated by TGF-ß1 in both young and aged HFB. Conclusions 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-ß1.

Ropivacaine suppresses tumor biological characteristics of human hepatocellular carcinoma via inhibiting IGF-1R/PI3K/AKT/mTOR signaling axis

“…MTOR is a serine/threonine secondary phosphorylation kinase involved in cell survival protein synthesis and metabolism [ 26 ]. It has been reported that local anesthetic lidocaine or mepivacaine can impair human dermal fibroblast proliferation of elders by inhibiting IGF-1 R, which is the curial regulator of wound healing [ 27 ]. Studies have shown that the anesthetic agent bupivacaine induces apoptosis via the reactive oxygen species-mediated PI3K/Akt pathway [ 28 ], and lidocaine can block the signal transduction of PI3K/Akt to exert neuroprotective effects [ 29 ].…”

Lidocaine inhibits melanoma cell proliferation by regulating ERK phosphorylation

“…It has been reported that ropivacaine and lidocaine, which are members of the amino amide class of local anesthetics, inhibit fibroblast proliferation . In addition, lidocaine, which is one of the most commonly used local anesthetics, has been shown to inhibit the biosynthetic functions of aged human dermal fibroblasts . Furthermore, it has been reported that the antiproliferative activity of local anesthetics, in addition to inhibitory effects on cellular migration and invasion, also provide some benefits in the treatment of cancer .…”

Topical application of lidocaine or bupivacaine in the healing of surgical wounds in dogs

“…The single application performed in the transsurgical period, mimics a common practice in the surgical routine and may have been a determining factor for the absence of side effects in healing, as studies show that the longer the duration of administration, the greater the damage to healing 18 . Additionally, considering our results, we can suggest that the concentration of the drug used may have been adequate in preventing side effects.…”

“…One of the main concerns in the topical use of anesthetics involves the cytotoxic effect on inflammatory cells and fibroblasts in vitro 16 , 17 . According to Bentov 18 , the inhibitory effect on the proliferation of fibroblasts occurred only in aged cells. The results obtained in this study show that there are no differences observed macroscopically during the healing period and there were also no significant differences at the end of the ten-day period, assessed microscopically on the histopathological examination.…”