Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways

Abstract

Sivelestat sodium (SIV), a neutrophil elastase inhibitor, is mainly used for the clinical treatment of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). However, studies investigating the effects of SIV treatment of ALI are limited. Therefore, this study investigated the potential molecular mechanism of the protective effects of SIV against ALI. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with tumor necrosis factor α (TNF-α), and male Sprague-Dawley rats were intratracheally injected with Klebsiella pneumoniae (KP) and treated with SIV, ML385, and anisomycin (ANI) to mimic the pathogenetic process of ALI in vitro and in vivo, respectively. The levels of inflammatory cytokines and indicators of oxidative stress were assessed in vitro and in vivo. The wet/dry (W/D) ratio of lung tissues, histopathological changes, inflammatory cells levels in bronchoalveolar lavage fluid (BALF), and survival rates of rats were analyzed. The JNK/NF-κB (p65) and Nrf2/HO-1 levels in the HPMECs and lung tissues were analyzed by western blot and immunofluorescence analyses. Administration of SIV reduced the inflammatory factors levels, intracellular reactive oxygen species (ROS) production, and malondialdehyde (MDA) levels and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues. Meanwhile, SIV alleviated pathological injuries, decreased the W/D ratio, and inflammatory cell infiltration in lung tissue. In addition, SIV also inhibited the activation of JNK/NF-κB signaling pathway, promoted nuclear translocation of Nrf2, and upregulated the expression of heme oxygenase 1 (HO-1). However, ANI or ML385 significantly reversed these changes. SIV effectively attenuated the inflammatory response and oxidative stress. Its potential molecular mechanism was related to the JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition. This further deepened the understanding of the protective effects of SIV against ALI.

A neutrophil elastase inhibitor, sivelestat, attenuates sepsis-induced acute kidney injury by inhibiting oxidative stress

“…Remarkably, treatment with sivelestat led to a marked improvement in these kidney structural parameters. The observed effects of sivelestat in attenuating oxidative stress and restoring the pathological injury, as shown in the present study, is supported by the findings of Zhang et al [ 16 ]. In their study, the authors showed that sivelestat effectively mitigates acute lung injury, reducing the levels of inflammatory factors, ROS and MDA, while increasing the levels of SOD and GSH-Px in lung tissues, potentially via the molecular mechanisms of JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition.…”

“…Sivelestat is a selective inhibitor of neutrophil elastase (NE), which has been proved to reduce lung injury [ 12 , 13 ], systemic inflammatory response syndrome [ 14 ], and acute respiratory distress syndrome [ 14 ]. Other evidence shows that sivelestat can improve the survival rate of septic animals and reduce sepsis-related lung injury [ 15 , 16 ]. By a mouse models of ischemic AKI, a significant increase in NE expression in the renal cortex/proximal tubules was observed [ 17 ].…”

Global research progress of endothelial cells and ALI/ARDS: a bibliometric analysis

“…Although NF-κB and MPO are frequently co-assayed in research related to ALI/ARDS and ECs, direct evidence confirming whether NF-κB explicitly regulates MPO expression or activity is currently lacking ( Mao and Wu, 2022 ). Other key factors like “HO-1”, “VEGF/VEGFA”, and “STAT3/STAT5” are also related to NF-κB in ECs and ALI/ARDS research ( Huang et al, 2019 ; Zhang H. et al, 2023 ; Chang and Zhang, 2023 ). Despite these observed interactions in various studies, the intricate mechanisms and interplays remain a focus for future research.…”

Efficacy of Sivelestat Sodium in the Therapy of Critically ill Patients at high risk of developing ARDS due to SIRS: A Multicenter Prospective Study

“…Sivelestat sodium, a neutrophil elastase inhibitor, has shown promising results to attenuate ARDS [6]. The mechanism of sivelestat includes inhibition of nuclear factor-kappa B (NF-κB) activation, reduction of reactive oxygen species (ROS) production, and modulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [7]. These effects contribute to the suppression of proin ammatory cytokines and chemokines which are key mediators of ARDS pathogenesis [8].…”