• Thomais Markou and David J Chambers.
• Cardiac Surgical Research, Rayne Institute, King's College London, St Thomas' Hospital Campus, London, United Kingdom. Electronic address: thomais.markou@kcl.ac.uk.
• J. Thorac. Cardiovasc. Surg. 2014 Nov 1; 148 (5): 2335-44.

ObjectivesLung deflation and inflation during cardiac surgery with cardiopulmonary bypass contributes to pulmonary dysfunction postoperatively. Theophylline treatment for lung diseases has traditionally been thought to act by phosphodiesterase inhibition; however, increasing evidence has suggested other plausible mechanisms. We investigated the effects of deflation and reinflation on signaling pathways (p38-mitogen-activated protein kinase [MAPK], extracellular signal-regulated kinase 1 and 2 [ERK1/2], and Akt) and whether theophylline influences the deflation-induced lung injury and associated signaling.MethodsIsolated rat lungs were perfused (15 mL/min) with deoxygenated rat blood in bicarbonate buffer and ventilated. After 20 minutes' equilibration, the lungs were deflated (60 minutes, aerobic perfusion 1.5 mL/min), followed by reinflation (60 minutes, anaerobic reperfusion 15 mL/min). Compliance, vascular resistance, and kinase phosphorylation were assessed during deflation and reinflation. The effects of SB203580 (50 μM), a p38-MAPK inhibitor, and theophylline (0.083 mM [therapeutic] or 3 mM [supratherapeutic]) on physiology and signaling were studied.ResultsDeflation reduced compliance by 44% compared with continuously ventilated lungs. p38-MAPK and Akt phosphorylation increased (three to fivefold) during deflation and reinflation, and ERK1/2 phosphorylation increased (approximately twofold) during reinflation. SB203580 had no effect on lung physiology or ERK1/2 and Akt activation. Both theophylline doses increased cyclic adenosine monophosphate, but only 3 mM theophylline improved compliance. p38-MAPK phosphorylation was not affected by theophylline; 0.083 mM theophylline inhibited reinflation-induced ERK1/2 phosphorylation (72%±3%); and 3 mM theophylline inhibited Akt phosphorylation during deflation (75%±5%) and reinflation (87%±4%).ConclusionsLung deflation and reinflation stimulates differential p38-MAPK, ERK1/2, and Akt activation, suggesting a role in lung injury during cardiopulmonary bypass. However, p38-MAPK was not involved in the compromised compliance. A supratherapeutic theophylline dose protected lungs against deflation-induced injury and was associated with inhibition of phosphoinositide 3-kinase/Akt rather than phosphodiesterase.Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

43 keywords...

hide…