Lidocaine Reduces Neutrophil Recruitment by Abolishing Chemokine-Induced Arrest and Transendothelial Migration in Septic Patients

Abstract

The inappropriate activation, positioning, and recruitment of leukocytes are implicated in the pathogenesis of multiple organ failure in sepsis. Although the local anesthetic lidocaine modulates inflammatory processes, the effects of lidocaine in sepsis are still unknown. This double-blinded, prospective, randomized clinical trial was conducted to investigate the effect of lidocaine on leukocyte recruitment in septic patients. Fourteen septic patients were randomized to receive either a placebo (n = 7) or a lidocaine (n = 7) bolus (1.5 mg/kg), followed by continuous infusion (100 mg/h for patients >70 kg or 70 mg/h for patients <70 kg) over a period of 48 h. Selectin-mediated slow rolling, chemokine-induced arrest, and transmigration were investigated by using flow chamber and transmigration assays. Lidocaine treatment abrogated chemokine-induced neutrophil arrest and significantly impaired neutrophil transmigration through endothelial cells by inhibition of the protein kinase C-θ while not affecting the selectin-mediated slow leukocyte rolling. The observed results were not attributable to changes in surface expression of adhesion molecules or selectin-mediated capturing capacity, indicating a direct effect of lidocaine on signal transduction in neutrophils. These data suggest that lidocaine selectively inhibits chemokine-induced arrest and transmigration of neutrophils by inhibition of protein kinase C-θ while not affecting selectin-mediated slow rolling. These findings may implicate a possible therapeutic role for lidocaine in decreasing the inappropriate activation, positioning, and recruitment of leukocytes during sepsis.

Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

“…Some of the genes affected in the G q reactome by rare SNVs have been shown to be involved in sepsis. Thus, PKCθ ( PRKCQ ) has been demonstrated in septic patients to impair chemokine-induced arrest and endothelial transmigration of neutrophils (Berger et al, 2014). G2A ( GPR132 ) is activated by commendamide, a metabolite of human commensal bacteria (Cohen et al, 2015) and pretreatment of mice with G2A-specific antibody inhibited lysophosphatidylcholine (LPC)-induced protection from cecal ligation and puncture (CLP) lethality and inhibited the LPC-mediated bactericidal activity of neutrophils in response to E. coli ingestion (Yan et al, 2004).…”

Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to β2-integrin dependent responses of equine neutrophils

“…The clinical benefit of minimizing neutrophil mediated tissue injury has been demonstrated in animal models of sepsis, ischemia-reperfusion injury, acute and chronic airway disease and arthritis (Kurtel et al, 1992; Fujishima and Aikawa, 1995; Moore et al, 1995; Kraan et al, 2000; Cazzola et al, 2012; Uriarte et al, 2013; Berger et al, 2014). However, most patients that would benefit from therapies targeting neutrophil migration would not realistically have an opportunity for “pretreatment” prior to neutrophil activation.…”

Does mitigating pain decrease the risk of infection? The interactions between nociception and immune function

“…Lidocaine has been shown to locally modulate the inflammatory response and relieve pain. Berger et al (2014) recently investigated the systemic effects of lidocaine on recruitment of leukocytes in adult patients with sepsis in a small randomized double-blind clinical trial (n ¼ 14) including bolus of lidocaine 1.5 mg/ kg versus saline followed by continuous weight based infusion over 48 h. Lidocaine reduced chemokine-induced neutrophils arrest and stopped transmigration of neutrophils which may reduce tissue injury associated with sepsis. Selectin mediating slow-rolling of neutrophils were preserved.…”