Isoflurane Ameliorates Acute Lung Injury by Preserving Epithelial Tight Junction Integrity

Abstract

Background Isoflurane may be protective in pre-clinical models of lung injury but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. We hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome. Methods Wild-type mice were treated with isoflurane one hour after exposure to nebulized endotoxin (n=8) or saline control (n=9) then allowed to recover for 24 hrs prior to mechanical ventilation (MV, tidal volume 15 mL/kg, 2 hrs) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane one hour after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo. Results Mice treated with isoflurane following exposure to inhaled endotoxin and prior to MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice following treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e. zona occludens 1) that was rescued by isoflurane treatment. Conclusions Isoflurane rescued lung injury induced by a two-hit model of endotoxin exposure followed by MV by maintaining the integrity of the alveolar-capillary barrier possibly by modulating the expression of a key tight junction protein.

Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy

“…51 In contrast, lower concentrations, as used here, have been reported to protect heart, kidney, and brain tissue from ischemic injury. 56 The mechanisms underlying the BBBprotecting effect of isoflurane are not known, but could be attributed to its capacity to inhibit calcium influx into endothelial cells, 57,58 reduce adhesion of neutrophils to endothelial cells, 59,60 preserve tight junction expression, 61 and inhibit neuroinflammation. 54 Consistent with our results in the paraoxon model, isoflurane was reported to decrease BBB leakage in a rat stroke model 55 and subarachnoid hemorrhage.…”

“…54 Consistent with our results in the paraoxon model, isoflurane was reported to decrease BBB leakage in a rat stroke model 55 and subarachnoid hemorrhage. 56 The mechanisms underlying the BBBprotecting effect of isoflurane are not known, but could be attributed to its capacity to inhibit calcium influx into endothelial cells, 57,58 reduce adhesion of neutrophils to endothelial cells, 59,60 preserve tight junction expression, 61 and inhibit neuroinflammation. 48 Only few previous studies succeeded in discovering therapies that prevent epilepsy in rodent models.…”

Peri‐operative pulmonary dysfunction and protection

“…Volatile anaesthetics may protect lung function by modulating the inflammatory response through inhibition of pro‐inflammatory mediators. Volatile anaesthetics protect the lungs as well as the heart against ischaemia and reperfusion injury . Inflammation following one‐lung ventilation is less after volatile anaesthesia compared with propofol anaesthesia and volatile agents might also reduce the composite rate of adverse effects .…”

Inhalation Sedation in Subjects With ARDS Undergoing Continuous Lateral Rotational Therapy

“…In this study we describe the successful use of isoflurane sedation with the AnaConDa system in 19 subjects being treated with continuous lateral rotational therapy for respiratory failure. This strategy was feasible, with theoretical advantages including bronchodilation, 6,7 cardiovascular 13 and lung-protective effects, 14,15 good control of the level of sedation, 16,17 and the ability to achieve deep sedation. We compared 19 isoflurane-sedated subjects with 19 subjects sedated via the intravenous route using propofol or midazolam and observed significantly decreased opioid consumption, deeper sedation, more spontaneous breathing, a decreased ⌬ P (peak inspiratory pressure Ϫ PEEP), and hemodynamically stable conditions after 24 h isoflurane versus propofol/midazolam.…”