Effects of sevoflurane on lung epithelial permeability in experimental models of acute respiratory distress syndrome

Abstract

Background Preclinical studies in acute respiratory distress syndrome (ARDS) have suggested that inhaled sevoflurane may have lung-protective effects and clinical trials are ongoing to assess its impact on major clinical outcomes in patients with ARDS. However, the underlying mechanisms of these potential benefits are largely unknown. This investigation focused on the effects of sevoflurane on lung permeability changes after sterile injury and the possible associated mechanisms. Methods To investigate whether sevoflurane could decrease lung alveolar epithelial permeability through the Ras homolog family member A (RhoA)/phospho-Myosin Light Chain 2 (Ser19) (pMLC)/filamentous (F)-actin pathway and whether the receptor for advanced glycation end-products (RAGE) may mediate these effects. Lung permeability was assessed in RAGE−/− and littermate wild-type C57BL/6JRj mice on days 0, 1, 2, and 4 after acid injury, alone or followed by exposure at 1% sevoflurane. Cell permeability of mouse lung epithelial cells was assessed after treatment with cytomix (a mixture of TNFɑ, IL-1β, and IFNγ) and/or RAGE antagonist peptide (RAP), alone or followed by exposure at 1% sevoflurane. Levels of zonula occludens-1, E-cadherin, and pMLC were quantified, along with F-actin immunostaining, in both models. RhoA activity was assessed in vitro. Results In mice after acid injury, sevoflurane was associated with better arterial oxygenation, decreased alveolar inflammation and histological damage, and non-significantly attenuated the increase in lung permeability. Preserved protein expression of zonula occludens-1 and less increase of pMLC and actin cytoskeletal rearrangement were observed in injured mice treated with sevoflurane. In vitro, sevoflurane markedly decreased electrical resistance and cytokine release of MLE-12 cells, which was associated with higher protein expression of zonula occludens-1. Improved oxygenation levels and attenuated increase in lung permeability and inflammatory response were observed in RAGE−/− mice compared to wild-type mice, but RAGE deletion did not influence the effects of sevoflurane on permeability indices after injury. However, the beneficial effect of sevoflurane previously observed in wild-type mice on day 1 after injury in terms of higher PaO2/FiO2 and decreased alveolar levels of cytokines was not found in RAGE−/− mice. In vitro, RAP alleviated some of the beneficial effects of sevoflurane on electrical resistance and cytoskeletal rearrangement, which was associated with decreased cytomix-induced RhoA activity. Conclusions Sevoflurane decreased injury and restored epithelial barrier function in two in vivo and in vitro models of sterile lung injury, which was associated with increased expression of junction proteins and decreased actin cytoskeletal rearrangement. In vitro findings suggest that sevoflurane may decrease lung epithelial permeability through the RhoA/pMLC/F-actin pathway. Graphical Abstract

Research hotspots and evolving trends of barrier dysfunction in acute lung injury and acute respiratory distress syndrome

“…When faced with specific inflammatory triggers, a significant number of immune cells gather at the site of injury, initiating a sequence of signals that promote inflammation and release numerous proinflammatory substances that harm the lung epithelium [ 39 ]. Damage to epithelial cells involves the dissociation of intercellular junctions and increased paracellular permeability, a process that involves the dysregulation of tight junction proteins (e.g., occlusion band (ZO) proteins) or adhesion junction proteins (e.g., e-calmodulin) and actin cytoskeletal rearrangement [ 40 ]. Pulmonary microvascular endothelial cells play a key role in maintaining the functional integrity of the endothelial barrier [ 41 ].…”

“…Considering the critical role of RhoA and PI3K-AKT signaling pathways in the endothelial barrier, inhibition of RhoA or PI3K-AKT signaling pathways may serve as a potential therapeutic target for the treatment of ALI/ARDS. Some drugs, such as sevoflurane and oxidized berberine, have been found to reduce alveolar epithelial barrier damage and permeability via RhoA in experimental models, ultimately preventing ALI progression [ 40 , 60 ].…”

Pectolinarigenin ameliorated airway inflammation and airway remodeling to exhibit antitussive effect

“…It is well known that cough in healthy individuals is a physiological defense mechanism to clear the airways of foreign particles and excessive bronchial secretions, and is a common symptom of several respiratory diseases [1]. Chronic cough can be debilitating, as the resulting distress can significantly impair the quality of life of patients [2,3]. Although most cases of cough are associated with infection, diagnostic tests for cough are made difficult by the long list of differential diagnoses.…”