Hydromorphone Protects against CO2 Pneumoperitoneum-Induced Lung Injury via Heme Oxygenase-1-Regulated Mitochondrial Dynamics.

Jia Shi,Cui Li,Shu-An Dong,Si-Meng He,Shi-Han Du,Li-Li Wu,Yan-Fang Zhang,Yuan Zhang,Hai-Bo Li,Jian-Bo Yu,Shane Thomas

doi:10.1155/2021/9034376

Jia Shi, Cui Li + Show 9 more

Open Access

https://doi.org/10.1155/2021/9034376

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Abstract

Various pharmacological agents and protective methods have been shown to reverse pneumoperitoneum-related lung injury, but identifying the best strategy is challenging. Herein, we employed lung tissues and blood samples from C57BL/6 mice with pneumoperitoneum-induced lung injury and blood samples from patients who received laparoscopic gynecological surgery to investigate the therapeutic role of hydromorphone in pneumoperitoneum-induced lung injury along with the underlying mechanism. We found that pretreatment with hydromorphone alleviated lung injury in mice that underwent CO2 insufflation, decreased the levels of myeloperoxidase (MPO), total oxidant status (TOS), and oxidative stress index (OSI), and increased total antioxidant status (TAS). In addition, after pretreatment with hydromorphone, upregulated HO-1 protein expression, reduced mitochondrial DNA content, and improved mitochondrial morphology and dynamics were observed in mice subjected to pneumoperitoneum. Immunohistochemical staining also verified that hydromorphone could increase the expression of HO-1 in lung tissues in mice subjected to CO2 pneumoperitoneum. Notably, in mice treated with HO-1-siRNA, the protective effects of hydromorphone against pneumoperitoneum-induced lung injury were abolished, and hydromorphone did not have additional protective effects on mitochondria. Additionally, in clinical patients who received laparoscopic gynecological surgery, pretreatment with hydromorphone resulted in lower serum levels of club cell secretory protein-16 (CC-16) and intercellular adhesion molecule-1 (ICAM-1), a lower prooxidant-antioxidant balance (PAB), and higher heme oxygenase-1 (HO-1) activity than morphine pretreatment. Collectively, our results suggest that hydromorphone protects against CO2 pneumoperitoneum-induced lung injury via HO-1-regulated mitochondrial dynamics and may be a promising strategy to treat CO2 pneumoperitoneum-induced lung injury.

Highlights

The benefits of laparoscopic techniques include decreased blood loss, shorter hospital stays, and faster resumption of daily activities [1]
We revealed that hydromorphone targets the balance of heme oxygenase-1 (HO-1)-mediated mitochondrial dynamics to alleviate CO2 pneumoperitoneum-induced lung injury
To investigate the effects of hydromorphone on CO2 pneumoperitoneum-induced lung injury, we developed a mouse model of pneumoperitoneum

Summary

Introduction

The benefits of laparoscopic techniques include decreased blood loss, shorter hospital stays, and faster resumption of daily activities [1]. The establishment of pneumoperitoneum during laparoscopic surgery often has detrimental effects on respiratory function, and this is especially true for the patients in the Trendelenburg position during gynecologic surgery [2, 3]. Oxidative stress induced by excess reactive oxygen species (ROS) was identified as one of the mechanisms of CO2 pneumoperitoneum-induced lung injury [4]. The most likely mechanisms of oxidative stress resulting from CO2 pneumoperitoneum are tissue traumarelated inflammation, ischemia/reperfusion due to changes in abdominal pressure, and diaphragmatic dysfunction [5]. Excess ROS can damage cellular components, aggravate inflammatory responses, and cause cellular injury and organ dysfunction [6].

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