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Endothelial barrier protection by local anesthetics: ropivacaine and lidocaine block tumor necrosis factor-α-induced endothelial cell Src activation.
- Source :
-
Anesthesiology [Anesthesiology] 2014 Jun; Vol. 120 (6), pp. 1414-28. - Publication Year :
- 2014
-
Abstract
- Background: Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase-Akt-nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability.<br />Methods: Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed.<br />Results: Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10 M for ropivacaine; IC50 = 5.864 × 10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10 M for ropivacaine; IC50 = 6.377 × 10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated.<br />Conclusions: Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory "side-effect" of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease.
- Subjects :
- Cells, Cultured
Endothelium, Vascular cytology
Endothelium, Vascular enzymology
Enzyme Activation drug effects
Enzyme Activation physiology
Humans
Lung drug effects
Lung enzymology
Microcirculation drug effects
Microcirculation physiology
Ropivacaine
Tumor Necrosis Factor-alpha administration & dosage
src-Family Kinases physiology
Amides pharmacology
Anesthetics, Local pharmacology
Endothelium, Vascular drug effects
Lidocaine pharmacology
Tumor Necrosis Factor-alpha antagonists & inhibitors
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-1175
- Volume :
- 120
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Anesthesiology
- Publication Type :
- Academic Journal
- Accession number :
- 24525631
- Full Text :
- https://doi.org/10.1097/ALN.0000000000000174