Impact of Prolonged Mechanical Ventilation on Ferroptosis in Renal Ischemia/Reperfusion Injury in Rats.

Fangfang Zhou,Yixin Chen,Qun Luo,Jianghua Chen,Yi Yang,Lianxin Luo

doi:10.1155/2020/6097516

Abstract

We here investigated the impact of mechanical ventilation (MV) time on ferroptosis in a rat renal ischemia/reperfusion injury (IRI) model. Thirty-two male adult Sprague Dawley rats were divided into four groups (n = 8/group): the sham group, IRI group, IRI+MV-4 h group, and IRI+MV-12 h group. Rats in the IRI group were subjected to 45 min bilateral renal ischemia. Rats in the IRI+MV groups were additionally mechanically ventilated with tracheal intubation after 45 min bilateral renal ischemia. Morphological changes associated with kidney injury and ferroptosis were assessed by hematoxylin and eosin staining and electron microscopy. Levels of the central regulator of ferroptosis, glutathione peroxidase 4 (GPX4), and lipid peroxidation markers 4-hydroxynonenal (4HNE) and superoxide dismutase 2 (SOD2) were determined in the kidney tissue by western blotting. Glutathione (GSH) levels were assessed in the serum and kidney homogenate. Scr levels in the IRI+MV-12 h group were significantly higher than those in the sham, IRI, and IRI+MV-4 h groups (all P < 0.001). Electron microscopy revealed the most pronouncedly abnormal mitochondrial morphology, suggestive of ferroptosis, in the IRI+MV-12 h group. The GPX4 and SOD2 protein levels progressively decreased in the following order: sham group > IRI group > IRI+MV-4 h group > IRI+MV-12 h group (P < 0.05 for all comparisons). By contrast, the 4HNE levels progressively increased in the kidney, with the highest values in the IRI+MV-12 h group (P < 0.05, vs. the IRI group and vs. the IRI+MV-4 h group). Further, the GSH levels in the serum and kidney homogenates were significantly reduced in the IRI+MV-12 h group (P < 0.01, vs. IRI group and vs. the IRI+MV-4 h group). A significant positive correlation was observed between the serum and kidney GSH levels (r2 = 0.542, P = 0.03). These observations suggested that prolonged MV may exacerbate renal function failure, already initiated by IRI, by ferroptosis. Depletion of GSH may contribute to this effect, which requires further investigation.

Highlights

Mechanical ventilation (MV) is associated with acute kidney injury (AKI) in the intensive care unit [1, 2]
The serum creatinine (Scr) levels showed no significant improvement in the ischemia/reperfusion injury (IRI) and IRI+MV-4 h groups (P = 0:397) (Figure 1)
These observations suggested that prolonged MV may exacerbate renal function failure, already initiated by IRI

Summary

Introduction

Mechanical ventilation (MV) is associated with acute kidney injury (AKI) in the intensive care unit [1, 2]. Hemodynamic changes, neurohormonal modifications, and systemic inflammation induced by MV may contribute to the development of AKI [3, 4]. Chiang, et al [6] demonstrated that MV with high tidal volume increases the generation of ROS, which acts as an initiating signal in the lung epithelium in response to increased cellular stretch. This suggests that ROS may play an important role in the pathogenesis of ventilator-induced lung injury

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Conclusion