Ventilation-induced activation of the mitogen-activated protein kinase pathway

Abstract

Mechanical ventilation of patients can be a life-saving treatment, but also imposes additional stress on the lung. Mitogen-activated protein kinases (MAPK) represent a family of protein kinases that become phosphorylated and activated by many different forms of stress.Using Western blot analysis, the present study analysed the effects of high distending pressure ventilation on the activation of the MAPK extracellular signal-related kinases (ERK)-1/2, c-Jun amino-terminal kinases (JNK) and p38 kinase, and on the MAPKactivated transcription factors c-Jun, ETS-like protein (Elk)-1 and activating transcription factor (ATF)-2.In adult rats, ventilation with high pressure (45/10 peak inspiratory pressure/positive end-expiratory pressure in cmH 2 O) for 30 or 60 min did not affect arterial oxygenation, but resulted in enhanced phosphorylation of ERK-1/2, JNK, c-Jun, Elk-1 and ATF-2 compared to normally ventilated (13/3) rats. The activation of ERK-1/2 and JNK was located to cells resembling alveolar type II cells. In addition, high pressure ventilation enhanced phosphorylation of the inhibitor of nuclear factor (NF)-kB and nuclear translocation of the transcription factor NF-kB. In isolated perfused mouse lungs, the MAPK/ERK kinase inhibitor U0126 prevented ventilation-induced activation of ERK-1/2 and Elk-1, but had no effect on ventilation-induced cytokine release.The present authors conclude that mechanical ventilation triggers specific signalling pathways, such as the mitogen-activated protein kinase and the nuclear factor-kB pathways, which may contribute to pulmonary inflammation and proliferation. Eur Respir J 2002; 20: 946-956.

Spillover of Cytokines and Reactive Oxygen Species in Ventilator-Induced Lung Injury Associated With Inflammation and Apoptosis in Distal Organs

“…[7][8][9][10][11]18 Our results further show that up-regulation of JNK, p38 MAPK, NF-KB, and caspase-3 is associated with inflammation and apoptosis in VILI; up-regulation of ERK is not associated with VILI.…”

“…8 Animal studies have demonstrated that high V T ventilation leads to increased neutrophil infiltration, activation of inflammatory cytokines, pulmonary inflammation, and diffuse alveolar damage via activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-KB) pathways. 9 Thus, VILI in animal models resembles the clinical features of ARDS. 10,11 Hyperventilation of a single lung in an isolated rat lung model leads to production of pro-inflammatory tumor necrosis factor alpha, increased permeability, and injury to the contralateral lung via circulating mediators, that is, biotrauma.…”

Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury

“…Ventilation leading to the nuclear translocation of NF-kB has been previously shown in cell culture, 41 in isolated perfused rat lungs, 42 and in animal lung injury induced by ventilation. 43 In this study, the activation of NF-kB was markedly attenuated by HCA accompanied by the reduction of oxidative stress from neutrophil-mediated injury. It has also been reported that hypercapnic acidosis inhibits the adhesion of endotoxin-induced neutrophils to pulmonary endothelial cells through attenuating IkB-a degradation, which in turn neutralizes the DNA-binding activity of NF-kB.…”

Modulation of Lipopolysaccharide-Induced Gene Transcription and Promotion of Lung Injury by Mechanical Ventilation

“…Transcriptional modulation by MV is supported by several published studies, which show that stretching lung-derived cells in vitro activates transcription factors, which promote proinflammatory cytokine transcription (19 -21). Activation of the transcription factors NF-B and AP-1 occurs when lungs are ventilated ex vivo and in vivo with moderate to large tidal volumes (5,22,23).…”

“…The role of GADD45 up-regulation in the pathogenesis of ALI is unknown; however, one function of GADD45 is to activate MEKK4, which in turn is an upstream regulator of JNK MAPK. JNK phosphorylates and activates members of the AP-1 family of transcription factors and has been implicated in ventilator-induced lung injury (23,28). Thus, it is a biologically plausible hypothesis that GADD45 may contribute to the pathogenesis of ALI, and further research into its role is warranted.…”