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

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.

Hydromorphone Mitigates Cardiopulmonary Bypass-Induced Acute Lung Injury by Repressing Pyroptosis of Alveolar Macrophages

“…Hydromorphone has been reported to induce HO-1 expression levels in lung injury (16), and we speculated that Hyd may attenuate CPB-induced ALI via upregulating Nrf2/HO-1 expression levels. Thereafter, we measured Nrf2/HO-1 expression levels in rat lung tissues and disclosed that CPB treatment induced the increases in Nrf2/HO-1 expression levels and Hyd treatment further promoted the increasing trends ( P < 0.01, Fig.…”

“…An existing study has reported the protective role of Hyd in CO 2 pneumoperitoneum-triggered lung injury (16), while it remains vague whether Hyd exerts the same protective role in CPB-induced ALI. To assess the impact of Hyd on lung function, we determined OI and RI in Hyd-pretreated rats after CPB induction.…”

“…Oral administration of Hyd can manage dyspnea after idiopathic pulmonary fibrosis (14). In addition, Hyd is demonstrated to protect against pulmonary inflammation and complications (15), and Hyd possesses a palliative effect on lung injury triggered by CO 2 pneumoperitoneum (16). However, the role of Hyd in NLRP3 inflammasome-mediated pyroptosis of AMs after CPB-induced ALI has not been reported.…”

“…The blockade of the Nrf2/HO-1 pathway accelerates pyroptosis of AMs in lung ischemia-reperfusion (I/R) injury (23). Notably, HO-1 expression levels can be upregulated by Hyd (16). As a consequence, we attempted to corroborate our hypothesis that Hyd can repress NLRP3 inflammasome-mediated pyroptosis of AMs to ameliorate CPB-induced ALI by regulating the Nrf2/HO-1 pathway, and the elucidation of this mechanism may refine the therapeutical practices for CPB-induced ALI.…”

Heme oxygenase-1 protects against endotoxin-induced acute lung injury depends on NAD+-mediated mitonuclear communication through PGC1α/PPARγ signaling pathway

“…Our previous studies have proved that HO-1 exhibits extensive protection both in LPS-stimulated RAW 264.7 cells and in a murine model of LPS-induced ALI by preserving mitochondrial dynamics through regulating fission and fusion [ 7 , 23 , 24 ]. Given the critical role of HO-1 on mitochondrial function and oxidative stress, we hypothesized that the protective effect of HO-1 might be associated with mitonuclear communication.…”