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Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling.
- Source :
-
BMC anesthesiology [BMC Anesthesiol] 2014 Jul 19; Vol. 14, pp. 57. Date of Electronic Publication: 2014 Jul 19 (Print Publication: 2014). - Publication Year :
- 2014
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Abstract
- Background: Acute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a "double-hit" model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling.<br />Methods: C57BL/6 (WT) and ICAM-1 (-/-) mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC).<br />Results: WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (pā=ā0.001), which was attenuated by ropivacaine (pā=ā0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation ("double-hit") increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3-4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 (-/-) mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI.<br />Conclusions: Ropivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability.
- Subjects :
- Acute Lung Injury etiology
Animals
Caveolin 1 genetics
Disease Models, Animal
Endothelial Cells drug effects
Endothelial Cells metabolism
Humans
Inflammation drug therapy
Inflammation pathology
Intercellular Adhesion Molecule-1 genetics
Lipopolysaccharides toxicity
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation drug effects
Pulmonary Edema prevention & control
Ropivacaine
Signal Transduction drug effects
Ventilator-Induced Lung Injury prevention & control
src-Family Kinases metabolism
Acute Lung Injury drug therapy
Amides pharmacology
Anesthetics, Local pharmacology
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2253
- Volume :
- 14
- Database :
- MEDLINE
- Journal :
- BMC anesthesiology
- Publication Type :
- Academic Journal
- Accession number :
- 25097454
- Full Text :
- https://doi.org/10.1186/1471-2253-14-57