Lidocaine and its Analogues Inhibit IL-5-Mediated Survival and Activation of Human Eosinophils

Abstract

Eosinophils and cytokines active on eosinophils, especially IL-5, are believed to be critically involved in chronic allergic diseases. IL-5 activates eosinophils and enhances their survival in vitro by delaying apoptosis. In this study, we found that lidocaine and six analogues blunt responses of eosinophils to IL-5. Lidocaine and its derivatives inhibit IL-5-mediated eosinophil survival in a concentration-dependent manner (IC50 = 110 μM for 30 pg/ml IL-5). At suboptimal lidocaine concentrations, the eosinophil survival response to IL-5 shifts and more IL-5 is required to maintain survival. The inhibitory effect requires at least 24-h exposure of eosinophils to lidocaine, and the protein kinase C activator, PMA, completely reverses the inhibition. A multiparameter flow-cytometric analysis shows that lidocaine hastens the apoptosis of eosinophils normally delayed by IL-5. Lidocaine does not affect IL-5R expression or IL-5-induced protein tyrosine phosphorylation. Lidocaine also inhibits eosinophil survival mediated by IL-3 or granulocyte-macrophage CSF, although less potently than that mediated by IL-5. Furthermore, lidocaine inhibits eosinophil superoxide production stimulated by IL-5, granulocyte-macrophage CSF, or IL-3, but not that stimulated by platelet-activating factor, immobilized IgG, or PMA. Lidocaine and its derivatives show novel immunomodulatory properties and are able to blunt eosinophil responses to cytokines in addition to their local anesthetic or antiarrhythmic properties. Thus, lidocaine and its derivatives may represent a new class of therapeutic agents to treat patients with allergic diseases.

Effects of Lidocaine-Derived Organic Compounds on Eosinophil Activation and Survival

“…However, only compound EI341 inhibited PAF-induced eosinophil migration. IL-5 time-dependently induced superoxide production and lidocaine (10 µM) reduced superoxide production, as reported previously [19]. After 4 h of treatment, compounds EI137 and EI341 strongly reduced IL-5-induced superoxide production (Figure 5).…”

“…IL-5 also induces the phosphorylation of ERK, MAPK, JNK, and activating transcription factor 2 [23]. Although lidocaine inhibits IL-5-induced survival and superoxide prediction, it is not involved in the phosphorylation of protein tyrosine kinase or other transcription factors [19]. Lidocaine analog compounds EI137 and EI341 significantly inhibited the expression of phosphorylated ERK1/2 but not total ERK1/2 (Figure 7).…”

Monophasic versus biphasic hyaluronic acid filler for correcting nasolabial folds: a systematic review and meta‐analysis

“…Similarly, a recent systematic review demonstrated a significant reduction in the 30‐min injection site pain with lidocaine‐containing HA fillers 36 . Lidocaine incorporation with HA fillers has also been linked with less injection‐associated bruising and swelling by inhibiting the activation of eosinophils after the injection 22,42 . However, Raspaldo et al found no evidence of NLFs asymmetry in patients who received HA fillers with or without lidocaine at long‐term follow‐up (76 weeks), indicating that lidocaine incorporation does not increase the longevity of HA fillers 43 …”

Lidocaine ameliorates intestinal barrier dysfunction in irritable bowel syndrome by modulating corticotropin‐releasing hormone receptor 2

“…[28][29][30] Furthermore, lidocaine possesses multiple functions, including reducing the release of oxygen free radicals, inhibiting neutrophil adhesion and aggregation, and stabilizing cell membranes, thereby exerting anti-inflammatory effects in various stages of the inflammatory response. 31,32 These findings suggest that lidocaine may exert its beneficial effects by modulating sensory signaling pathways involved in pain perception within the gastrointestinal tract. However, whether lidocaine can protect intestinal barrier in IBS deserves further exploration.…”

“…Several studies have demonstrated that intrarectal lidocaine administration effectively reduces abdominal pain and improves visceral hyperalgesia in IBS patients 28–30 . Furthermore, lidocaine possesses multiple functions, including reducing the release of oxygen free radicals, inhibiting neutrophil adhesion and aggregation, and stabilizing cell membranes, thereby exerting anti‐inflammatory effects in various stages of the inflammatory response 31,32 . These findings suggest that lidocaine may exert its beneficial effects by modulating sensory signaling pathways involved in pain perception within the gastrointestinal tract.…”