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.
Background
Several studies have shown an association between plasma homocysteine levels and chronic obstructive pulmonary disease (COPD). It is not clear whether there is a causal association. A two-sample Mendelian randomization (MR) based method was used to further explore the causal association between plasma homocysteine and COPD.
Methods
Several studies have shown an association between plasma homocysteine levels and COPD. It is not clear whether there is a causal association.we performed a second data analysis using pooled data from published genome-wide association studies (GWASs) .we used genome-wide meta-analysis (n = 44147) to obtain genome-wide single nucleotide polypeptides (SNPs) associated with plasma homocysteine levels as instrumental variables. We used two-sample MR to study plasma homocysteine and COPD and COPD related diseases. MR analysis was performed by the random effects inverse variance weighting method and heterogeneity tests and pleiotropy tests were performed to evaluate the robustness of our findings.
Results
By two-sample MR analysis, We did not find causal associations between genetically predicted plasma homocysteine levels and COPD and COPD related diseases. In COPD hospital admissions,(OR = 1.06,95%CI 0.91–1.24,P = 0.42),asthma/COPD,(OR = 0.97,95%CI 0.89–1.06, P = 0.55),COPD related to chronic (opportunist) infection(OR = 1.50,95%CI 0.57–3.99,P = 0.41),COPD/asthma/ILD-related pneumonia or pneumonia-derived (OR = 0.93,95%CI 0.86–1.02,P = 0.13),COPD-related respiratory insufficiency(OR = 1.00,95%CI 0.7–1.44,P = 0.99), no heterogeneity and horizontal pleiotropy werefound.
Conclusions
Our study shows that genetically predicted plasma homocysteine levels are not causally associated with COPD, contrary to previous observational findings.As homocysteine is known to have deleterious effects on endothelial function and vascular homeostasis, further studies are needed to investigate whether additional factors mediate the association between homocysteine and COPD.
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