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-1β, 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-1β, 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-1β, 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-1β (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.

Objective:To investigate the protective effect of β- blocker (esmolol) on myocardia and toll-like receptor 4 (TLR4) inflammatory pathway in septic rats.Methods:Sixty male Wistar rats were randomly (random number) divided into the shame group, sepsis group (CLP group), esmolol group (CLP+ES group) and TLR4 inhibitor group (CLP+TAK-242 group) with 15 rats in each group. Cecal exploration was performed in the shame group, and cecal ligation and perforation (CLP) was performed in the CLP group, CLP+ES group and CLP+TAK-242 group. The CLP+ES group received intraperitoneal injection of esmolol diluent 20 mg/kg 12 h after CLP. The CLP+TAK-242 group was given intraperitoneal injection of TAK-242 3 mg/kg at the same time point as above. The shame group and CLP group were given the same amount of normal saline. Rats in all groups were sacrificed 24 h after operation, and the samples were collected and processed. The pathological changes of myocardium were observed by hematoxylin - eosin staining. The expression of TLR4, myeloid differentiation protein 88 (MyD88) and nuclear factor -κB (NF-κB) in myocardial tissue were observed by immunohistochemistry. Masson staining was used to observe the expression of fibers and inflammatory factors in myocardial tissue. The protein expressions of TLR4, MyD88, NF-κB and aspartic acid specific cysteine protease 1 (caspase-1) were detected by Western blot. Serum levels of cardiac troponin I (cTn-I), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by enzyme-linked immunosorbent assay (ELISA).Results:Compared with the shame group, myocardial injury, fibrosis and inflammatory cell infiltration were significantly aggravated in the CLP group, and the levels of myocardial injury index cTn-I and inflammatory mediators TNF-α, IL-6 and IL-1β were significantly increased [(8.70±0.22) vs. (4.41±0.31), (445.57±9.13) vs. (219.60±5.52), (165.55±2.18) vs. (93.47±3.37), (124.12±2.59) vs. (67.63±6.04),all P<0.05]. Compared with the CLP group, myocardial injury was significantly reduced in the CLP+ES group and CLP+TAK-242 group, and the levels of inflammatory transmitters were significantly reduced [(5.38±0.18) and (5.37±0.13) vs. (8.70±0.22), (322.73±7.63) and (300.58±17.47) vs. (445.57±9.13), (121.28±5.44) and (120.30±4.95) vs. (165.55±2.18), (102.60±4.09) and (105.08±7.21) vs. (124.12±2.59), all P<0.05]. Western blot analysis showed that the protein expression levels of TLR4, MyD88, NF-κB and caspase-1 in the CLP group were significantly higher than those in the shame group [(1.79±0.15) vs. (1.15±0.04), (4.70±0.30) vs. (3.87±0.10), (0.35±0.04) vs. (0.18±0.02), (2.27±0.29) vs. (1.15±0.07), all P<0.05], while the protein expression levels in the CLP+ES group and CLP+TAK-242 group were significantly lower than those in the CLP group [(1.31±0.16) and (1.18±0.14) vs. (1.79±0.15), (1.50±0.16) and (1.46±0.19) vs. (2.27±0.29), (0.27±0.02) and (0.24±0.01) vs. (0.35±0.04), (1.50±0.16) and (1.46±0.19) vs. (2.27±0.29), all P<0.05]. Conclusions:β-blocker can reduce myocardial injury and inhibit the expression of inflammatory mediators in septic rats by blocking the inflammatory response mediated by TLR4 signaling pathway.

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.

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, β 1 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.