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

Background: Sivelestat, a selective inhibitor of neutrophil elastase (NE), can mitigate sepsis-related acute lung injury. However, the role of sivelestat in inhibiting oxidative stress and attenuating sepsis-related acute kidney injury (AKI) remains unclear. Here, we reported the effects of sivelestat against oxidative stress-induced AKI by suppressing the production of oxidative stress indicators. Materials and methods: A male Sprague-Dawley rat model of sepsis was established by cecal ligation and puncture (CLP). Sivelestat or normal saline was administered into jugular vein with a sustained-release drug delivery system. Indicators of inflammation and AKI, including white blood cells (WBC), neutrophils, lymphocytes, C-reactive proteins (CRP), procalcitonin (PCT), blood urea nitrogen (BUN), creatinine (Cr) and uric acid (UA), were assessed at 24 h post-sivelestat treatment. Indicators of liver injury, including direct bilirubin (DBIL), indirect bilirubin (IBIL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were also assessed at 24 h post-sivelestat treatment. Indicators of oxidative stress, including superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), were assessed at 12 h and 24 h post-sivelestat treatment. At 24 h post-sivelestat treatment, H&E staining of kidney and liver tissue was performed to observe pathological alterations. Results: At 24 h post normal saline or sivelestat (0.2 g/kg body weight) treatment, WBC, neutrophil, CRP, PCT, MDA, BUN, Cr, UA, AST, ALT, DBIL and IBIL were increased, while SOD and GSH-Px were decreased, in septic rats treated with normal saline compared with that in non-septic rats treated with normal saline (all p < 0.05). The changes of these indicators were reversed in septic rats treated with sivelestat compared with that in septic rats treated with normal saline (all p < 0.05). Similar results were found regarding the levels of oxidative stress indicators at 12 h post-sivelestat treatment. The degenerative histopathological changes in both kidney and liver tissues were ameliorated upon sivelestat treatment. Conclusions: Sivelestat plays a protective role in sepsis-related AKI by inhibiting oxidative stress. Our study reveals a possible therapeutic potential of sivelestat for oxidative stress-induced AKI.

Epidemiology and Risk Factors of Community-Associated Bloodstream Infections in Zhejiang Province, China, 2017-2020.

Purpose: Community-associated bloodstream infection (CA-BSI) is increasing in many community settings. However, the clinical significance and epidemiology of CA-BSI present in hospital admissions in China are not well established. In this work, we identified the risk factors in outpatients presenting with CA-BSI, and investigate the role of procalcitonin (PCT) and hypersensitive C-reactive protein (CRP) in diagnosing different types of the pathogen in patients with acute CA-BSI. Methods: A retrospective study enrolling 219 outpatients with CA-BSI from The Zhejiang People's Hospital from January 2017 to December 2020 was performed. Susceptibility of the isolates obtained from these patients was examined. Subjecting receiver operating characteristic curves (ROC) were constructed to analyze the specificity and sensitivity of PCT, CRP, and WBC in determining infections caused by different bacterial genera. Risk factors for CA-BSI in the emergency setting were analyzed using essential information and simple identification of other pathogenic bacterial species through rapidly tested biomarkers. Results: A total of 219 patients were included in the selection criteria, of which 103 were infected with Gram-positive bacteria (G+) and 116 with Gram-negative bacteria (G-). The PCT was significantly higher in the GN-BSI group than in the GP-BSI group, while no significant difference was observed between the two groups for CRP. Subjecting ROC curves were constructed to analyze WBC, CRP, and PCT, and the area under the curve (AUC) of the PCT in this model was 0.6661, with sensitivity = 0.798 and specificity = 0.489. Conclusion: The PCT between the GP-BSI group and the GN-BSI group was significantly different. By combining the knowledge of clinicians and the clinical signs of patients, PCT should be utilized as a supplementary approach to initially determine pathogens and direct medication in the early stages of clinical practice.

Oxidative stress-related circulating miRNA-27a is a potential biomarker for diagnosis and prognosis in patients with sepsis.

BACKGROUND: Oxidative stress plays a critical role on the processes of sepsis, and several microRNAs have been identified that may regulate the occurrence of oxidative stress. However, the relation between oxidative stress-related microRNA 27a (miR-27a) and sepsis is unknown. The present study aimed to determine the value of circulating miR-27a for the diagnosis and prognosis of sepsis. METHODS: This retrospective study included 23 patients with sepsis and 25 without sepsis treated at the emergency intensive care unit (EICU) or our institution between January 2019 and January 2020. Levels of circulating miR-27a and levels of oxidative stress-related indicators were measured and compared between sepsis and non-sepsis patients. Receiver operating characteristic (ROC) curve analysis was used to determine diagnostic efficiency of miR-27a. RESULTS: Circulating miR-27a levels in sepsis patients were higher than those in non-sepsis patients (p < 0.05), and levels were significantly higher in patients that died than those that lived (p < 0.05). In patients with sepsis, circulating miR-27a level was positively correlated with serum malondialdehyde (MDA) level (rs = 0.529, p = 0.007), and negatively correlated with serum glutathione peroxidase (GSH-Px) level (rs = - 0.477, p = 0.016). No significant correlation was observed between circulating miR-27a and serum superoxide dismutase (SOD) in sepsis patients (rs = - 0.340, p = 0.096). The area under the ROC curve (AUC) of miR-27a level for prediction of sepsis was 0.717 (p = 0.009) and for 28-day mortality was 0.739 (p = 0.003). CONCLUSIONS: This study showed that circulating miR-27a level is correlated with oxidative stress and mortality in patients with sepsis, and may serve as a potential non-invasive molecular biomarker.

Bone marrow-derived mesenchymal stem cells attenuate myocardial ischemia-reperfusion injury via upregulation of splenic regulatory T cells.

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is the main pathological manifestation of cardiovascular diseases such as myocardial infarction. The potential therapeutic effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and the participation of regulatory T cells (Tregs) in MIRI remains to be defined. METHODS: We used the experimental acute MIRI that was induced in mice by left ascending coronary ischemia, which were subsequently randomized to receive immunoglobulin G (IgG) or anti-CD25 antibody PC61 with or without intravenously injected BM-MSCs. The splenectomized mice underwent prior to experimental MIRI followed by intravenous administration of BM-MSCs. At 72 h post-MIRI, the hearts and spleens were harvested and subjected to cytometric and histologic analyses. RESULTS: CD25+Foxp3+ regulatory T cells were significantly elevated after MIRI in the hearts and spleens of mice receiving IgG + BM-MSCs and PC61 + BM-MSCs compared to the respective control mice (all p < 0.01). This was accompanied by upregulation of interleukin 10 and transforming growth factor ß1 and downregulation of creatinine kinase and lactate dehydrogenase in the serum. The post-MIRI mice receiving BM-MSCs showed attenuated inflammation and cellular apoptosis in the heart. Meanwhile, splenectomy compromised all therapeutic effects of BM-MSCs. CONCLUSION: Administration of BM-MSCs effectively alleviates MIRI in mice through inducing Treg activation, particularly in the spleen.