Interactions between Cytosolic Phospholipase A2 Activation and Mitochondrial Reactive Oxygen Species Production in the Development of Ventilator-Induced Diaphragm Dysfunction

Shao-Ping Li,Xian-Long Zhou,Yan Zhao,Ming-Xia Yu,Xiao-Jun Wei,Rui-Ning Liu

doi:10.1155/2019/2561929

Abstract

Cytosolic phospholipase A2 (cPLA2) has been reported to be critical for infection-induced mitochondrial reactive oxygen species (ROS) production and diaphragm dysfunction (DD). In the present study, we aim to investigate whether cPLA2 was involved in ventilator-induced diaphragm dysfunction (VIDD). Our results showed that mechanical ventilation (MV) induced cPLA2 activation in the diaphragm with excessive mitochondrial ROS generation and muscle weakness. Specific inhibition of cPLA2 with CDIBA resulted in decreased mitochondrial ROS levels and improved diaphragm forces. In addition, mitochondria-targeted antioxidant MitoTEMPO attenuated ventilator-induced mitochondrial oxidative stress and downregulated cPLA2 activation in vivo. Both CDIBA and MitoTEMPO were able to attenuate protein degradation, muscle atrophy, and weakness following prolonged MV. Furthermore, laser Doppler imaging showed that MV decreased diaphragm tissue perfusion and induced subsequent hypoxia. An in vitro study also demonstrated a positive association between cPLA2 activation and mitochondrial ROS generation in C2C12 cells cultured under hypoxic condition. Collectively, our study showed that cPLA2 activation positively interacts with mitochondrial ROS generation in the development of VIDD, and ventilator-induced diaphragm hypoxia serves as a possible contributor to this positive feedback loop.

Highlights

Diaphragm dysfunction (DD) occurring following long-term mechanical ventilation (MV), which is widely known as ventilator-induced mechanical ventilation (VIDD), is a great concern in the modern era of MV
Heart rate, and body temperature were monitored throughout the experiment, and no significant differences were observed between ventilation groups at the end of study (p > 0 05, respectively)
The major findings of this study can be summarized as follows: (1) prolonged MV for 12 hours is able to induce Cytosolic phospholipase A2 (cPLA2) activation in the rat diaphragm; (2) ventilator-induced cPLA2 activation positively interacts with mitochondrial reactive oxygen species (ROS) generation, which promotes the development of ventilator-induced diaphragm dysfunction (VIDD); and (3) MV decreases diaphragm tissue perfusion and induces expression of HIF-1α, and diaphragm hypoxia possibly contributes to cPLA2 activation and mitochondrial ROS generation following MV

Summary

Introduction

Diaphragm dysfunction (DD) occurring following long-term mechanical ventilation (MV), which is widely known as ventilator-induced mechanical ventilation (VIDD), is a great concern in the modern era of MV. In vitro measurements of diaphragm contractile properties suggest that the decrease in contractility is an early and progressive phenomenon [3]. CMV induces diaphragm atrophy as early as 12 hours after induction of MV, and the atrophy develops rapidly [4]. In addition to protein synthesis, proteolysis plays a dominant role in diaphragm atrophy after CMV [5]. The onset of oxidative injury is rapid and long-lasting in animal MV models and has been demonstrated to be a key upstream regulator of protease system activation that contributes to diaphragm muscle atrophy and weakness [6]

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