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

BMC Anesthesiology

Research Article

Alain Borgeat¹  Andreia Z Chignalia²  Ruben G Koshy²  David E Schwartz²  E Gina Votta-Velis³  Guochang Hu⁴  Maricela Castellon⁴  Randal O Dull⁵  Richard D Minshall⁶  Tobias Piegeler⁷  Beatrice Beck-Schimmer⁸ 

[1] Department of Anesthesiology, Balgrist University Hospital, Zurich, Switzerland;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Department of Anesthesiology, Jesse Brown VA Medical Center, Chicago, IL, USA;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Department of Pharmacology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Department of Pharmacology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Department of Bioengineering, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Department of Pharmacology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Department of Bioengineering, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Center for Lung and Vascular Biology, University of Illinois Hospital > Health Sciences System, Chicago, IL, USA;Department of Anesthesiology, University of Illinois Hospital > Health Sciences System, 835 S. Wolcott Ave (m/c 868), 60612, Chicago, IL, USA;Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland;Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland;

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

DOI  :  10.1186/1471-2253-14-57

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

来源: Springer

【 摘 要 】

BackgroundAcute 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.MethodsC57BL/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).ResultsWT 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.ConclusionsRopivacaine 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】

Unknown   
© Piegeler et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.