Fig. 8.
Summary of proposed mechanism of inhibition of inflammatory Src signaling by local anesthetics. Local anesthetics (LA) inhibit recruitment of p85 regulatory subunit (p85) of phosphatidyl-inositide-3 kinase (PI3K) to tumor necrosis factor-α (TNFα) receptor 1 (TNF-R1), thus preventing PI3K activation and subsequent signaling involving phosphorylation/activation of Akt, endothelial nitric oxide synthase (eNOS), nitric oxide (NO) generation, and Src activation. Inhibition of Src-dependent intercellular adhesion molecule-1 (ICAM-1) phosphorylation blocks the increase in neutrophil binding, and the inhibition of direct and indirect (via the phosphorylation of caveolin-1) Src-dependent destabilization of adherens junctions attenuates endothelial barrier disruption and hyperpermeability. An alternative pathway (gray arrows) leading to Src activation might involve protein kinase C (PKC), nicotinamide adenine dinucleotide phosphate-oxidase (NOX), and the generation of superoxide anions (O2−).