Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling

BMC Anesthesiology

Tobias Piegeler⁶  Randal O Dull¹  Guochang Hu²  Maricela Castellon²  Andreia Z Chignalia⁴  Ruben G Koshy⁴  E Gina Votta-Velis⁵  Alain Borgeat⁷  David E Schwartz⁴  Beatrice Beck-Schimmer⁶  Richard D Minshall³ 

[1] Department of Bioengineering, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA

[2] Department of Pharmacology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA

[3] Center for Lung and Vascular Biology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA

[4] Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), Chicago, IL 60612, USA

[5] Department of Anesthesiology, Jesse Brown VA Medical Center, Chicago, IL, USA

[6] Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland

[7] Department of Anesthesiology, Balgrist University Hospital, Zurich, Switzerland

关键词: Src protein tyrosine kinase;    Caveolin-1;    Endothelium;    Local anesthetics;    Ventilator-induced lung injury;    ARDS;    Acute lung injury;   

Others  :  1084627
DOI  :  10.1186/1471-2253-14-57

 received in 2013-11-15, accepted in 2014-07-08,  发布年份 2014

【 摘 要 】

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.

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).

Results

WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). 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.

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.

【 授权许可】

   
2014 Piegeler et al.; licensee BioMed Central Ltd.

【 图 表 】

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