Endothelial barrier protection by local anesthetics: ropivacaine and lidocaine block tumor necrosis factor-α-induced endothelial cell Src activation

Vascular inflammation is thought to underlie the high morbidity and mortality of diseases such as acute lung injury, acute respiratory distress syndrome (ARDS), diabetes mellitus, and cancer.1–5 Therapeutic options are limited to the treatment of symptoms (e.g., lung-protective ventilation in patients with ARDS) rather than the cause of endothelial barrier dysfunction.6 Vascular hyperpermeability and endothelial barrier dysfunction play key roles in the pathogenesis of vascular injury due to inflammation.6,7 The proinflammatory cytokine tumor necrosis factor-α (TNFα) activates c-Src protein tyrosine kinase (Src) and increases endothelial permeability.8 Although the exact mechanism of TNFα-induced Src activation is not completely understood, it has been demonstrated that endothelial nitric oxide synthase (eNOS)–mediated nitric oxide production downstream of phosphatidylinositide 3-kinase (PI3K)-dependent activation of Akt9–11 and CaM kinase II induce Src activation.10,12 TNFα-induced PI3K activation is thought to be initiated by recruitment of PI3K regulatory subunit p85 to TNF-receptor-1 (TNF-R1) upon agonist binding.13 Downstream signaling of activated Src includes phosphorylation of intercellular adhesion molecule-1 (ICAM-1) and caveolin-1, which have both been shown to contribute to the development of the endothelial injury and inflammatory hyperpermeability.14–17 Experimental evidence indicates that amide-linked local anesthetics such as ropivacaine and lidocaine exhibit beneficial properties during the pathogenesis of acute lung injury: they were proven to attenuate experimental (endotoxin-induced) lung inflammation in vivo and in vitro18,19 as well as neutrophil-dependent acute lung injury induced by N-formyl-l-leucine-methionyl-l-phenylalanine20,21 In addition, we recently demonstrated inhibition of TNFα-induced Src activation by ropivacaine and lidocaine in a human lung cancer cell line in vitro.22 We therefore hypothesized that amide-linked local anesthetics, such as ropivacaine and lidocaine, may attenuate inflammatory Src signaling and subsequent ICAM-1 and caveolin-1 phosphorylation by disrupting the PI3K–Akt–nitric oxide signaling pathway, thus blocking Src-dependent vascular inflammation and hyperpermeability of the endothelium. The results of the current study indicate a novel anti-inflammatory mechanism by which ropivacaine and lidocaine may minimize endothelial injury during the pathogenesis of acute lung injury or ARDS.