[Sivelestat protects acute kidney injury by inhibiting the PI3K/AKT pathway in septic rats].

OBJECTIVE: To explore the protective effect of sivelestat (SV) against sepsis-induced acute kidney injury (AKI) and its molecular mechanism. METHODS: According to the random number table method, 64 male Wistar rats were divided into sham operation group (Sham group), sepsis due to cecal ligation and puncture group (CLP group), low dose of SV treatment group (SL group, 50 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), and high dose of SV treatment group (SH group, 100 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), with 16 rats in each group. 48 hours after CLP, the 48-hour survival of rats were recorded, all rats were sacrificed and samples were harvested. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of kidney injury molecule-1 (KIM-1), interleukins (IL-1ß, IL-6), tumor necrosis factor-α (TNF-α) and neutrophil elastase (NE). Hematoxylin-eosin (HE) staining was used to observe histopathological changes and assess renal tubule injury score. Masson staining was used to detect the collagen volume fraction (CVF) of kidney tissue. Western blotting was used to detect the protein expressions of phosphatidylinositol 3-kinase (PI3K), phosphorylation PI3K (p-PI3K), protein kinase B (AKT), phosphorylation AKT (p-AKT), nuclear factor-κB p65 (NF-κB p65) and NE. The protein expressions of p-PI3K, p-AKT, NF-κB p65 were detected by immunohistochemistry. RESULTS: Compared with Sham group, the 48-hour survival rate of CLP group was significantly reduced. Histopathological results showed that large tubular epithelial cells and brush margins were shed, tubular casts were formed, some tubular atrophy, glomerular hyperemia, renal interstitial inflammatory cell infiltration and increased renal tubular injury score. Renal interstitial fibrosis was obvious and CVF increased. The levels of KIM-1, IL-1ß, IL-6, TNF-α and NE in serum were significantly elevated in the CLP group. The proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly increased in kidney tissue. It suggested that septic rats had renal injury and the PI3K/AKT inflammatory pathway was activated. Compared with CLP group, there was no significant difference in 48-hour survival in SL group and SH group (68.75%, 75.00% vs. 56.25%, both P > 0.05), but kidney injury was significantly relieved. Specifically: renal tubular injury score and CVF significantly decreased [tubular injury score: 2 (1, 2), 1 (1, 1) vs. 2 (2, 3); CVF: (22.36±0.86)%, (18.74±1.05)% vs. (58.38±0.79)%, all P < 0.05]; the serum levels of KIM-1, IL-1ß, IL-6, TNF-α and NE also decreased significantly [KIM-1 (ng/L): 145.03±8.88, 117.58±7.02 vs. 158.22±12.00; IL-1ß (ng/L): 108.32±9.00, 92.98±8.06 vs. 133.78±8.48; IL-6 (ng/L): 124.33±10.11, 115.42±8.17 vs. 165.19±5.70; TNF-α (ng/L): 321.56±19.29, 289.68±21.57 vs. 424.88±22.76, NE (mol/L): 93.84±9.14, 75.01±10.56 vs. 113.45±6.39, all P < 0.05]; the proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly decreased (p-PI3K/PI3K: 0.93±0.06, 0.67±0.04 vs. 1.27±0.08; p-AKT/AKT: 0.78±0.09, 0.47±0.05 vs. 0.96±0.12; NF-κB p65/GAPDH: 1.43±0.13, 0.85±0.08 vs. 1.88±0.17; NE/GAPDH: 1.45±0.06, 0.91±0.04 vs. 1.71±0.08, all P < 0.05), the positive expressions of p-PI3K, p-AKT and NF-κB p65 in kidney tissue were decreased [p-PI3K positive expression area: (13.36±1.84)%, (8.03±1.12)% vs. (21.56±1.20)%; p-AKT positive expression area: (21.57±0.91)%, (15.21±2.76)% vs. (30.81±2.12)%; NF-κB p65 positive expression area: (25.17±1.38)%, (17.07±2.11)% vs. (37.85±2.50)%, all P < 0.05]. Serum inflammatory factor level, and PI3K/AKT pathway related protein, NF-κB p65, NE protein expression level and p-PI3K, p-AKT, NF-κB p65 positive area and other indicators in renal tissue in SH group were further lower than those in SL group (all P < 0.05). CONCLUSIONS: SV can ameliorate sepsis-induced AKI. The mechanism may be related to the inhibition of PI3K/AKT pathway, and high dose of SV has better efficacy.

Clinical Utility of the Sivelestat for the Treatment of ALI/ARDS: Moving on in the Controversy?

Acute respiratory distress syndrome (ARDS) is a serious condition that can arise following direct or indirect acute lung injury (ALI). It is heterogeneous and has a high mortality rate. Supportive care is the mainstay of treatment and there is no definitive pharmacological treatment as yet. In nonclinical studies, neutrophil elastase inhibitor sivelestat appears to show benefit in ARDS without inhibiting the host immune defense in cases of infection. In clinical studies, the efficacy of sivelestat in the treatment of ARDS remains controversial. The currently available evidence suggests that sivelestat may show some benefit in the treatment of ARDS, although large, randomized controlled trials are needed in specific pathophysiological conditions to explore these potential benefits.

Effect of Sivelestat in the Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

Background: The efficacy of neutrophil elastase inhibitor sivelestat in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remains controversial. A systematic review and meta-analysis were performed in accordance with the PRISMA guidelines assess the effect of sivelestat on ALI/ARDS patients, different studies were included. Methods: Electronic databases, National Knowledge Infrastructure (CNKI), Wan fang data, VIP, PubMed, Embase, Springer, Ovid and the Cochrane Library were searched using the following key words: ("Sivelestat" OR "Elaspol") AND ("ARDS" OR "adult respiratory distress syndrome" OR "acute lung injury"). All databases published from January 2000 to August 2022. The treatment group was treated with sivelestat and the control group was given normal saline. The outcome measurements include the mortality of 28-30 days, mechanical ventilation time, ventilation free days, intensive care unit (ICU) stays, oxygenation index (PaO2/FiO2) on day 3, the incidence of adverse events. The literature search was conducted independently by 2 researchers using standardized methods. We used the Cochrane risk-of-bias tool to assess the quality of the included studies. Mean difference (MD), Standardized mean difference (SMD) and relative risk (RR) were calculated using random effects model or fixed effects model. All statistical analyses were performed using RevMan software 5.4. Results: A total of 2050 patients were enrolled in 15 studies, including 1069 patients in treatment group and 981 patients in the control group. The results of the meta-analysis showed that: compared with the control group, sivelestat can reduce the mortality of 28-30 days (RR = 0.81, 95% CI = 0.66-0.98, p = 0.03) and the incidence of adverse events (RR = 0.91, 95% CI = 0.85-0.98, p = 0.01), shortened mechanical ventilation time (SMD = - 0.32, 95% CI = - 0.60 to - 0.04, p = 0.02) and ICU stays (SMD = - 0.72, 95% CI = - 0.92 to - 0.52, p < 0.00001), increased the ventilation free days (MD = 3.57, 95% CI = 3.42-3.73, p < 0.00001) and improve oxygenation index (PaO2/FiO2) on day 3 (SMD = 0.88, 95% CI = 0.39-1.36, p = 0.0004). Conclusions: Sivelestat can not only reduce the mortality of ALI/ARDS patients within 28-30 days and the incidence of adverse events, shorten the mechanical ventilation time and ICU stays, increase ventilation free days, but also improve the oxygenation index of patients on days 3, which has a good effect on the treatment of ALI/ARDS. These findings need to be verified in large-scale trials.

[Research progress of ferroptosis related pathways in sepsis].

Sepsis is a disease caused by pathogenic microorganisms such as bacteria, which is characterized by host response disorder, organ dysfunction and high mortality. In early stage, it is mainly inflammatory reaction, howeverin late stage, it is mainly immunosuppression. It is a little pale to explain the poorprognosis caused by sepsis only by severe infection and immunosuppression. From the perspective of the absolute mortality of sepsis over the world, the battle against sepsis has not won a comprehensive victory. It has been 10 years since "ferroptosis" was formally proposed by Dixionet al. in 2012. The research areahas never decreased from the initial tumor related diseases to nervous system diseases and cardiovascular system diseases, and has made some progress. At present, in the context of sepsis, it is found that ferroptosis plays an increasingly important role in organ dysfunction, and also has an important impact on the treatment and prognosis of the disease. This article summarizes the related pathways and interventions of several major ferroptosis at present, in order to have a more comprehensive understanding of the pathogenesis of sepsis, seek new treatment targets, optimize diagnosis and treatment strategies, and improve survival rate, quality of life and clinical prognosis.

[Research advance of the mechanism and treatment of septic cardiomyopathy].

Sepsis is a life-threatening organ dysfunction caused by dysregulation of the body's response to infection. It is one of the common and serious complications in clinically critical patients with trauma, burn, shock, infection, etc., with high morbidity and mortality. Although the treatment of sepsis has made great achievements in clinical practice, the mortality of patients with sepsis is still increasing due to its secondary complications. Septic cardiomyopathy (SCM) is one of the major complications that threaten septic patient's life. SCM refers to myocardial dysfunction with the aggravation of the primary disease, which is manifested by biventricular dilatation accompanied by a decrease in left ventricular ejection fraction (LVEF). It is one of the major complications that threaten the life of patients with sepsis. The existing research shows that the mechanism of SCM includes myocardial mitochondrial dysfunction, myocardial cell apoptosis, calcium circulation disorder and its treatment including conventional treatment, ß1 receptor blocker treatment and traditional Chinese medicine treatment,etc. This paper reviewed the pathogenesis of SCM and its related, in order to provide references for the rational diagnosis and treatment of SCM.