Protective signalling mechanisms in the lung induced by open-lung ventilation strategies

摘要

The acute respiratory distress syndrome (ARDS) is the major reason for morbidity and mortality in patients treated in intensive care units. Direct or indirect pulmonary injury can lead to ARDS. Mechanical ventilation is the basis of treatment of patients with ARDS. Mechanical ventilation may induce by itself further damage of the lung tissue. To minimise the risk of subsequent ventilator-induced lung injury (VILI), “protective ventilation” strategies were developed. The mechanisms of lung protection due to protective ventilation settings are largely unknown. The molecular mechanisms of lung protection were examined in lung tissue from a saline lavage ARDS rat model. Rats were divided into three groups: one without induction of lung injury, one with induction of lung injury and low positive end- expiratory pressure (PEEP) ventilation, and one group with induction of lung injury and high PEEP ventilation (“open lung”). From these studies Akt has emerged as a candidate mediator of lung protective pathways during mechanical ventilation of lungs with an “open lung” concept. Akt inhibits the pro-apoptotic factor p53 directly. Further, Akt inactivates AMP-activated protein kinase alpha (AMPKalpha) and glycogen synthase kinase 3beta (GSK3beta). The kinase AMPKalpha normally activates p53, and thus, Akt can also inhibit p53 indirectly. Active GSK3beta leads to a degradation of beta-catenin leading to cell membrane instability and apoptosis. This route of apoptosis induction is also subverted by Akt. That there was a reduced degree of apoptosis under protective “open lung” ventilation was indicated by western blot analyses for the apoptosis marker cleaved poly-ADP- ribose polymerase (PARP), where the amount of cleaved PARP was lowest in the rat group ventilated with the “open lung” strategy. These findings were corroborated by real-time PCR analyses of the pro-apoptotic p53-inducible genes APAF1, CDKN1A and GADD45A, which presented highest expression levels in the low PEEP-ventilated rat group, suggesting p53-dependent apoptotic pathways in VILI. Finally, immunohistochemical examinations revealed that the type I pneumocytes were more affected by apoptosis than type II pneumocytes during mechanical ventilation of the lung.