Sivelestat Sodium Research Articles

A comparative analysis of sivelestat sodium hydrate and ulinastatin combination therapy in the treatment of sepsis with acute respiratory distress syndrome

ObjectiveThis comparative analysis aimed to investigate the efficacy of Sivelestat Sodium Hydrate (SSH) combined with Ulinastatin (UTI) in the treatment of sepsis with acute respiratory distress syndrome (ARDS).MethodsA control group and an observation group were formed with eighty-four cases of patients with sepsis with ARDS, with 42 cases in each group. The control group was intravenously injected with UTI based on conventional treatment, and the observation group was injected with SSH based on the control group. Both groups were treated continuously for 7 days, and the treatment outcomes and efficacy of both groups were observed. The Murray Lung Injury Score (MLIS), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) were compared. Changes in respiratory function, inflammatory factors, and oxidative stress indicators were assessed. The occurrence of adverse drug reactions was recorded.ResultsThe total effective rate in the observation group (95.24%) was higher than that in the control group (80.95%) (P < 0.05). The mechanical ventilation time, intensive care unit (ICU) hospitalization time, and duration of antimicrobial medication in the observation group were shorter and multiple organ dysfunction syndrome incidence was lower than those in the control group (P < 0.05). The mortality rate of patients in the observation group (35.71%) was lower than that in the control group (52.38%), but there was no statistically significant difference between the two groups (P > 0.05). MLIS, SOFA, and APACHE II scores in the observation group were lower than the control group (P < 0.05). After treatment, respiratory function, inflammation, and oxidative stress were improved in the observation group (P < 0.05). Adverse reactions were not significantly different between the two groups (P > 0.05).ConclusionThe combination of SSH plus UTI improves lung injury and pulmonary ventilation function, and reduces inflammation and oxidative stress in patients with sepsis and ARDS.

Sivelestat sodium inhibits neutrophil elastase to regulate intrahepatic biliary mucin 5AC expression

To explore whether sivelestat sodium could reduce the expression of mucin 5AC (MUC5AC) in intrahepatic bile duct epithelial cells by inhibiting neutrophil elastase (NE) and thus provide new potential therapeutic ideas for the treatment of intrahepatic bile duct stone (IBDS). (1) Bioinformatics analysis: differential gene analysis was performed on gallbladder stone cholecystitis sequencing data based on the gene expression omnibus (GEO) to screen for significantly different genes related to neutrophils and mucins. The search tool for the retrieval of interacting genes database (STRING) was used for protein interaction analysis to predict whether there was an interaction between NE and MUC5AC genes. (2) Animal experiment: a total of 18 male SD rats were divided into the sham-operated group, cholangitis model group and sivelestat sodium treatment group according to the random number table method, with 6 rats in each group. The cholangitis rat model was established by a one-time injection of 1.25 mg/kg lipopolysaccharide (LPS) into the right anterior lobe of the liver of rats in combination with the pre-experiment; the liver of the sham-operated group was injected with an equal volume of saline. After the modelling, 100 mg/kg of sivelestat sodium was injected into the tail vein of the cevalexin treatment group once a day for 5 days, and an equal volume of saline was injected into the tail vein of the sham-operated group and the cholangitis model group. Two weeks later, the rats were euthanized and their liver and bile duct tissues were taken. The pathological changes in the liver and bile duct tissues were observed under the light microscope. Immunohistochemical staining was used to detect the expressions of NE and MUC5AC in liver and bile duct tissues. The protein expressions of NE, MUC5AC and Toll-like receptor 4 (TLR4) were detected by Western blotting. (3) Cell experiment: primary human intrahepatic biliary epithelial cell line (HiBEpiC) was divided into blank control group, NE group (10 nmol/L NE), NE+sivelestat sodium low dose group (10 nmol/L NE+1×10-8 g/L sivelestat sodium 1 mL), NE+sivelestat sodium medium dose group (10 nmol/L NE+1×10-7 g/L sivelestat sodium 1 mL), NE+sivelestat sodium high dose group (10 nmol/L NE+1×10-6 g/L sivelestat sodium 1 mL). Cells were collected after 48 hours of culture, and EdU was performed to detect the proliferative activity of cells; enzyme linked immunosorbent assay (ELISA) and Western blotting were performed to detect the expression of MUC5AC in cells. (1) Bioinformatics analysis: the NE gene (ELANE) had a reciprocal relationship with MUC5AC. (2) Animal experiment: light microscopy showed that hepatocyte edema, hepatocyte diffuse point and focal necrosis, confluent area fibrous tissue and intrahepatic bile ducts hyperplasia and inflammatory cell infiltration in the cholangitis model group; hepatic lobule structure of sivelestat sodium treatment group was clear, and the degree of peripheral inflammatory cell infiltration was reduced compared with the cholangitis model group. Immunohistochemical staining showed that the expressions of NE and MUC5AC were increased in the cholangitis model group compared with the sham-operated group, and the expressions of NE and MUC5AC were decreased in the sivelestat sodium group compared with the cholangitis model group [NE (A value): 5.23±2.02 vs. 116.67±23.06, MUC5AC (A value): 5.40±3.09 vs. 23.81±7.09, both P < 0.05]. Western blotting showed that the protein expressions of NE, MUC5AC, and TLR4 in the hepatic biliary tissues of the cholangitis model group were significantly higher than those of the sham-operated group; and the protein expressions of NE, MUC5AC, and TLR4 in the liver biliary tissues of the sivelestat sodium treatment group were significantly higher than those of the sham-operated group (NE/β-actin: 0.38±0.04 vs. 0.70±0.10, MUC5AC/β-actin: 0.37±0.03 vs. 0.61±0.05, TLR4/β-actin: 0.39±0.10 vs. 0.93±0.15, all P < 0.05). (3) Cell experiment: fluorescence microscopy showed that the proliferation of HiBEpiC cells in each group was good, and there was no significant difference in the proportion of positive cells. ELISA and Western blotting showed that the expressions of MUC5AC in cells of the NE group were significantly higher than those of the blank control group. The expressions of MUC5AC in the NE+different dose of sivelestat sodium group were significantly lower than those in the NE group, and showed a decreasing trend with the increase of sevastatin sodium concentration, especially in the highest dose group [MUC5AC (μg/L): 3.46±0.20 vs. 6.33±0.52, MUC5AC/β-actin: 0.45±0.07 vs. 1.75±0.10, both P < 0.05]. LPS can upregulate the expression of NE and MUC5AC in rats with cholangitis, while sodium sivelestat can reduce the expression of MUC5AC in in intrahepatic biliary epithelial cells by inhibiting NE, providing a new direction for the treatment of IBDS.

The beneficial effects of neutrophil elastase inhibitor on gastrointestinal dysfunction in sepsis.

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.

Efficacy Analysis and Prognostic Impact of Sivelestat Sodium in Coronavirus Disease 2019-Related Acute Respiratory Distress Syndrome.

This study aimed to evaluate the efficacy of sivelestat sodium on mortality, oxygenation index, and serum markers in patients with acute respiratory distress syndrome (ARDS) associated with Coronavirus Disease 2019 (COVID-19). A retrospective analysis was conducted on adult inpatients admitted to the Intensive Care Unit (ICU). The study compared clinical characteristics, laboratory indices, and mortality rates between patients treated with and without sivelestat sodium. Cox regression analysis was employed to assess the effect of sivelestat sodium on the risk of death, oxygenation index, and improvement of serum markers in patients with COVID-19-associated ARDS. A total of 110 patients with COVID-19-associated ARDS were included, with 45 patients in the sivelestat group and 65 patients in the control group. The overall patient mortality rate was 69.1%, with 62.2% in the sivelestat group and 73.8% in the control group. After five days of treatment, the median change from baseline in the oxygenation index was 21 mmHg in the medicated group and -31 mmHg in the control group (p < 0.05). Analysis of the oxygenation index as a clinical endpoint event showed a significantly higher rate of improvement in the sivelestat group compared to the control group (57.8% vs. 38.5%, p < 0.05), and the odds of raising the oxygenation index after treatment were 2.05 times higher in the sivelestat group than in the control group (HR = 2.05, 95%CI: 1.02-4.15, p < 0.05). Among patients with a baseline oxygenation index < 200 mmHg, patients in the sivelestat group had an 86% lower risk of death compared to the control group (HR = 0.14, 95%CI: 0.02-0.81, p < 0.05). Sivelestat sodium demonstrated a significant improvement in the oxygenation index of patients with COVID-19-associated ARDS and was found to considerably reduce the risk of death in patients with a baseline oxygenation index of <200 mmHg.

Perioperative oxygenation impairment related to type a aortic dissection.

Type A aortic dissection (TAAD) is a life-threatening disease with high mortality and poor prognosis, usually treated by surgery. There are many complications in its perioperative period, one of which is oxygenation impairment (OI). As a common complication of TAAD, OI usually occurs throughout the perioperative period of TAAD and requires prolonged mechanical ventilation (MV) and other supportive measures. The purpose of this article is to review the risk factors, mechanisms, and treatments of type A aortic dissection-related oxygenation impairment (TAAD-OI) so as to improve clinicians' knowledge about it. Among risk factors, elevated body mass index (BMI), prolonged extracorporeal circulation (ECC) duration, higher inflammatory cells and stored blood transfusion stand out. A reduced occurrence of TAAD-OI can be achieved by controlling these risk factors such as suppressing inflammatory response by drugs. As for its mechanism, it is currently believed that inflammatory signaling pathways play a major role in this process, including the HMGB1/RAGE signaling pathway, gut-lung axis and macrophage, which have been gradually explored and are expected to provide evidences revealing the specific mechanism of TAAD-OI. Numerous treatments have been investigated for TAAD-OI, such as nitric oxide (NO), continuous pulmonary perfusion/inflation, ulinastatin and sivelestat sodium, immunomodulation intervention and mechanical support. However, these measures are all aimed at postoperative TAAD-OI, and not all of the therapies have shown satisfactory effects. Treatments for preoperative TAAD-OI are not currently available because it is difficult to correct OI without correcting the dissection. Therefore, the best solution for preoperative TAAD-OI is to operate as soon as possible. At present, there is no specific method for clinical application, and it relies more on the experience of clinicians or learns from treatments of other diseases related to oxygenation disorders. More efforts should be made to understand its pathogenesis to better improve its treatments in the future.

Sivelestat improves acute lung injury by inhibiting PI3K/AKT/mTOR signaling pathway.

To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL). A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway. ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium. Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway.

Synthesis of Related Substances of Sivelestat Sodium

Synthesis of Related Substances of Sivelestat Sodium

Effects of intravenous sivelestat sodium on prevention of acute respiratory distress syndrome in patients with sepsis: study protocol for a double-blind multicentre randomised controlled trial

IntroductionSepsis is one of the most common risk factors for acute respiratory distress syndrome (ARDS). Neutrophil elastase (NE) is believed to be an important mediator of ARDS. When sepsis occurs,...

Sivelestat sodium for treatment of patients with COVID-19-associated acute respiratory distress syndrome in intensive care unit: a single-center retrospective cohort study

To investigate the effect of sivelestat sodium on survival, oxygenation index, and serum markers for infection in critically ill patients with COVID-19-associated acute respiratory distress syndrome (ARDS). This retrospectively study was performed among the critically ill patients with COVID-19-associated ARDS admitted in the intensive care unit (ICU) at Nanfang Hospital, Southern Medical University. We collected the clinical data of the patients on the first day of ICU admission and on the day of discharge and laboratory tests results of interleukin-6 (IL-6), C-reactive protein (CRP) and procalcitonin (PCT) and oxygenation index on days 1, 3 and 7 following ICU admission. Propensity-score matching was used to match the patients receiving sivelestat sodium to those without the treatment. Cox proportional hazards model and linear regression analysis were used to assess the association of sivelestat sodium treatment with in-hospital mortality and the length of hospital stay. A total of 199 patients with COVID-19-associated ARDS patients were included for data analysis. After propensity-score matching PSM, 35 patients receiving sivelestat sodium were matched to 70 patients without the treatment. Treatment with of sivelestat sodium was not associated with the reduction of in- hospital mortality (P=0.36), prolonged ICU stay (P=0.39), hospital stay (P=0.68) or improved oxygenation index (P>0.05) of the patients. No significant difference was found in serum CRP or PCT levels between the patients with and without sivelestat sodium treatment, but a significant reduction in IL-6 level was found in sivelestat sodium group (P=0.016). Sivelestat sodium treatment is not correlated with the reduction of mortality or length of hospital stay, but is associated with reduced serum IL-6 level in patients with COVID-19-associated ARDS.

Sivelestat sodium alleviated lipopolysaccharide-induced acute lung injury by improving endoplasmic reticulum stress

Acute lung injury (ALI) is a common inflammatory respiratory disorder characterized by a high incidence and mortality rate. This study aimed to investigate the potential therapeutic effects of the neutrophil elastase inhibitor Sivelestat sodium (SIV) in improving endoplasmic reticulum stress (ERS) while treating lipopolysaccharide (LPS)-induced ALI. An ALI model was established using LPS induction. The effects of SIV on ALI were observed both in vivo and in vitro, along with its impact on ERS. Lung tissue damage was assessed using Hematoxylin-eosin (H&E) staining. Lung edema was measured by the lung wet/dry weight ratio. The expression levels of protein kinase R-like ER kinase (PERK), Phospho-protein kinase R-like ER kinase (p-PERK), activating transcription factor 4 (ATF4), eukaryotic translation initiation factor 2α (EIF2a), phosphorylated α subunit of eukaryotic initiation factor 2α (P-EIF2a), and C/EBP homologous protein (CHOP) were analyzed by Western blotting in vivo and in vitro. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in Lung tissue samples supernatants were measured by ELISA. Oxidative stress markers were measured by ELISA. Apoptosis was measured using the TUNEL assay. Apoptosis-associated proteins B-cell lymphoma-2 (Bcl-2)、Bcl2-associated × (Bax)、caspase-3 were evaluated through Western blotting in vivo and in vitro. The expression levels of ERS-related proteins, including p-PERK, ATF4, P-EIF2a, and CHOP, were significantly increased in the LPS-induced ALI model. However, SIV markedly reduced the expression levels of these proteins, suppressing the LPS-induced ERS response. Further investigations revealed that SIV exerted a protective effect on ALI by alleviating lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress levels. However, when SIV was co-administered with Tunicamycin (TUN), TUN blocked the beneficial effects of SIV on ERS and reversed the protective effects of SIV on ALI. In conclusion, SIV alleviated lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress in LPS-induced ALI by improving ERS.

Endoplasmic Reticulum Stress is Involved in the Protective Effect of Sivelestat Sodium Hydrate (ONO-5046) in Spinal Cord Ischemia-Reperfusion Injury.

Postoperative complications of thoracoabdominal aortic aneurysm include paraplegia due to impaired blood flow in the spinal cord. Sivelestat sodium hydrate (ONO-5046), a specific neutrophil elastase inhibitor, can prevent neuropathy after ischemia-reperfusion of the spinal cord; however, the underlying mechanism remains unclear. Here, we examined whether ONO-5046 elicits its protective effects in spinal cord ischemia by affecting endoplasmic reticulum (ER) stress. Forty-five male Japanese white rabbits (weight 2.5-3.0 kg) were assigned to three groups: a sham control group (n = 5), and two other groups (n = 20, respectively; n = 5 each time point) that were subjected to spinal cord ischemia-reperfusion for 15 min and administered saline or ONO-5046 intravenously. From 8 h to 7 d after resumption of blood flow, a neurological evaluation, histological evaluation of the spinal cord, and immunohistochemical evaluation based on the expression of GRP78 and caspase12 were performed. Rabbits treated with ONO-5046 had fewer functional deficits and more surviving motor neurons after ischemia than did rabbits in the saline and control groups. In rabbits treated with ONO-5046, histological findings of the spinal cord showed a high number of viable motor nerves, whereas induction of GRP78, an ER stress response-related protein, was prolonged. Furthermore, caspase12 expression was activated by excessive ER stress and was downregulated in rabbits treated with ONO-5046, as compared with that in rabbits administered saline. ONO-5046 exerts a protective effect on the spinal cord by relieving ER stress during spinal cord ischemia.

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

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.

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

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.

Efficacy and safety of sivelestat sodium in patients with sepsis

To investigate the efficacy and safety of sivelestat sodium in patients with sepsis. The clinical data of 141 adult patients with sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Zhengzhou University from January 1, 2019 to January 1, 2022 were retrospectively analyzed. The patients were divided into the sivelestat sodium group (n = 70) and the control group (n = 71) according to whether they received sivelestat sodium or not. The efficacy indexes included oxygenation index, procalcitonin (PCT), C-reactive protein (CRP), white blood count (WBC), sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II) before and after 7 days of treatment, as well as ventilator supporting time, the length of ICU stay, the length of hospital stay and ICU mortality. The safety indicators included platelet count (PLT) and liver and kidney function. There were no significant differences in age, gender, underlying diseases, infection site, basic drugs, etiology, oxygenation index, biochemical indexes, SOFA and APACHE II scores between the two groups. Compared with the control group, the oxygenation index in 7 days was significantly increased [mmHg (1 mmHg ≈ 0.133 kPa): 233.5 (181.0, 278.0) vs. 202.0 (153.0, 243.0), P < 0.01], the levels of PCT, CRP, alanine aminotransferase (ALT) and APACHE II score were significantly decreased in the sivelestat sodium group [PCT (μg/L): 0.87 (0.41, 1.61) vs. 1.53 (0.56, 5.33), CRP (mg/L): 64.12 (19.61, 150.86) vs. 107.20 (50.30, 173.00), ALT (U/L): 25.0 (15.0, 43.0) vs. 31.0 (20.0, 65.0), APACHE II: 14 (11, 18) vs. 16 (13, 21), all P < 0.05]. However, there were no significant differences in SOFA, WBC, serum creatinine (SCr), PLT, total bilirubin (TBil), aspartate aminotransferase (AST) in 7 days between the sivelestat sodium group and the control group [SOFA: 6.5 (5.0, 10.0) vs. 7.0 (5.0, 10.0), WBC (×109/L): 10.5 (8.2, 14.7) vs. 10.5 (7.2, 15.2), SCr (μmol/L): 76.0 (50.0, 124.1) vs. 84.0 (59.0, 129.0), PLT (×109/L): 127.5 (59.8, 212.3) vs. 121.0 (55.0, 211.0), TBil (μmol/L): 16.8 (10.0, 32.1) vs. 16.6 (8.4, 26.9), AST (U/L): 31.5 (22.0, 62.3) vs. 37.0 (24.0, 63.0), all P > 0.05]. The ventilator supporting time and the length of ICU stay in the sivelestat sodium group were significantly shorter than those in control group [ventilator supporting time (hours): 147.50 (86.83, 220.00) vs. 182.00 (100.00, 360.00), the length of ICU stay (days): 12.5 (9.0, 18.3) vs. 16.0 (11.0, 23.0), both P < 0.05]. However, there were no significant differences in the length of hospital stay and ICU mortality between the sivelestat sodium group and the control group [the length of hospital stay (days): 20.0 (11.0, 27.3) vs. 13.0 (11.0, 21.0), ICU mortality: 17.1% (12/70) vs. 14.1% (10/71), both P > 0.05]. Sivelestat sodium is safe and effective in patients with sepsis. It can improve the oxygenation index and APACHE II score, reduce the levels of PCT and CRP, shorten ventilator supporting time and the length of ICU stay. No adverse reactions such as liver and kidney function injury and platelet abnormality are observed.

Neutrophil extracellular traps induce the bone erosion of gout

ObjectiveTo investigate the relationships between monosodium urate (MSU) crystals -induced neutrophil extracellular traps (NETs) and bone erosion in gout.MethodsAnimal models were used to study the relationship between NETs induced by MSU crystals and bone erosion. Neutrophils were treated with MSU crystals to induce NETs. The osteoblasts-like cells (OB) were then treated with NETs, and the supernatant was co-incubated with osteoclasts-like cells (OC). The NETs were digested with DNase, and the neutrophil elastase (NE) was inhibited with sivelestat sodium. Cell viability, mRNA, and protein expression were also assessed.ResultsAfter treating OB with NETs, the cell viability decreased. Yet, after digesting the DNA and inhibiting NE, the viability was moderately improved. The expression level of osteoprotegerin (OPG) and alkaline phosphatase (ALP) was up-regulated, while the expression level of receptor activator of nuclear factor kappa-B ligand (RANKL) was down-regulated in the sivelestat sodium + MSU group compared with MSU group. The number of OC was significantly elevated. In contrast, the number of OB was not increased in the tibia after establishing the gout model. The supernatant obtained from OB was treated with NETs promoting OC differentiation. The expression level of receptor activator of nuclear factor kappa-B (RANK), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (Cst K) was up-regulated in the MSU group compared with the normal control (NC) group.ConclusionNETs induced by MSU crystals could inhibit osteoblasts viability and enhance the activity of osteoclasts.

Myocardial protective effect of sivelestat sodium in rat models with sepsis-induced myocarditis.

The incidence of sepsis has been steadily increasing worldwide, and the heart is one of the target organs that can be easily damaged by sepsis. At present, antibiotics and organ function support are the main treatment options for sepsis and multiple system organ dysfunction, but are still under investigation. Fifty rats were randomly divided into the sham operation group, sepsis group, sivelestat sodium low-dose (L) group (administered with sivelestat sodium 1.6 mg/kg), sivelestat sodium middle-dose (M) group (administered with sivelestat sodium 4.8 mg/kg), and sivelestat sodium high-dose (H) group (administered with sivelestat sodium 10 mg/kg). Morphological changes of myocardial cells and the distribution of extracellular signal-regulated kinase (ERK)1/2 proteins were observed by light microscope. Serum troponin-T, creatine kinase isoenzyme MB, brain natriuretic peptide, interleukin (IL)-6, tumor necrosis factor-α, and IL-1β levels and changes in cardiac function indicators were measured. The protein expressions of Bax, Bcl-2, and ERK1/2 were detected by Western blotting. Compared with the sham operation group, the release of inflammatory factors in the sepsis group increased; the protein expressions of Bax, Bcl-2, and ERK1/2 increased; left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of LVP rise (+dp/dtmax) level decreased, whereas -dp/dtmax increased. In the sivelestat sodium groups, the release of inflammatory factors decreased; Bax expression decreased, whereas Bcl-2 and ERK1/2 protein expressions increased; LVSP, LVEDP, and +dp/dtmax increased, whereas -dp/dtmax decreased. In addition, all of these changes occurred in a dose-dependent manner. Sivelestat sodium can effectively lower the expressions of inflammatory factors and improve cardiac function. It can act on the ERK1/2 signaling pathway to exert its cardiomyocyte-protective effect, and the activation of this signaling pathway can offer potential treatment sites for septic myocarditis.

Efficacy and safety of sivelestat sodium for the treatment of inflammatory response in acute Stanford type A aortic dissection: a retrospective cohort study

Systemic inflammatory response syndrome (SIRS) after surgery for acute Stanford type A aortic dissection (ATAAD) via cardiopulmonary bypass (CPB) are strongly associated with mortality. Although the sivelestat sodium has been approved for the treatment of patients with acute lung injury, there is currently no enough evidence for improving inflammatory response and reducing the associated mortality. Our study aims to investigate the efficacy and safety of sivelestat sodium for the treatment of inflammatory response in acute Stanford type A aortic dissection. A total of 71 ATAAD patients who received surgical treatment at our center from January 2021 to December 2021 retrospectively reviewed. Patients were divided into the sivelestat sodium group and the control group. Clinical information including the postoperative oxygenation index (PaO2/FiO2), white blood cell (WBC) count, procalcitonin (PCT) level, interleukin-6 (IL-6) level, duration of ventilator use (hours), intensive care unit stay (days), and 28-day mortality rate, were collected. The statistical inference differences between the groups were compared using the non-paired Student's t-test, Wilcoxon rank sum test, chi squared test and repeated analysis of variance (ANOVA). There were no significant differences between the sivelestat sodium group and the control group in terms of baseline characteristics (all P>0.05). The mortality rate was decreased in the sivelestat sodium group than the control group (10% vs. 13.73%). The subgroup analysis showed that for patients with a mechanical ventilation duration >96 h, the 48-h oxygenation index (149±53 vs. 260±66, P=0.001), and the 72-h oxygenation index (165±66 vs. 288±95, P=0.002) were significantly lower in the control group than the sivelestat sodium group. And the postoperative WBC count (P=0.015) and PCT level (P=0.033) were significantly lower in the sivelestat sodium group than the control group in post-operative day 4. Sivelestat sodium can improves the postoperative oxygenation index and inflammatory response for ATAAD patients requiring mechanical ventilation for extended periods.

Comparative study of the protective effect of Xuebijing injection and Sivelestat sodium on acute lung injury/acute respiratory distress syndrome rats

To compare the protective effect of Xuebijing injection versus Sivelestat sodium on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rats. A total of 71 male Sprague-Dawley (SD) rats were randomly divided into the blank control group (n = 8), ALI/ARDS model group (n = 21), Xuebijing injection group (n = 21) and Sivelestat sodium group (n = 21). Rats in the blank control group were injected with normal saline while the other three groups were intravenously injected 25 mg/kg lipopolysaccharide (LPS) via the tail vein to establish ALI/ARDS model. After induction of ALI/ARDS model, the blank control group and ALI/ARDS model group were given intraperitoneal injection of an equal volume of normal saline twice a day. Rats in the Xuebijing injection group were given tail vein injection of 8 mL/kg Xuebijing injection twice a day, and those in the Sivelestat sodium group were given intraperitoneal injection of 100 mg/kg Sivelestat sodium three times a day. All rats were administered continuously for five days. During the experiment, the general status of rats was observed, and the weight and survival were recorded. At the end of the experiment, bronchoalveolar lavage fluid (BALF) of rats was collected for the detection of inflammatory cells and inflammatory factors. Histopathological changes of rats lung tissue were observed. Compared with the ALI/ARDS model group, the Xuebijing injection group and Sivelestat sodium group had significantly decreased white blood cell (WBC) count and percent of neutrophil (NEU%) [WBC (×109/L): 55.86±6.68, 49.96±6.76 vs. 73.13±7.35, NEU%: 0.459±0.077, 0.315±0.047 vs. 0.709±0.067, all P < 0.05], significantly increased percent of lymphocytes (LYM%: 0.412±0.067, 0.517±0.051 vs. 0.232±0.057, both P < 0.05), and reduced interleukin-6 (IL-6) level (ng/L: 295.2±39.7, 281.9±33.1 vs. 469.6±77.0) in BALF. However, there were no significant differences in these parameters between the Xuebijing injection group and Sivelestat sodium injection group (all P > 0.05). Survival rate at the end of experiment was higher in the Xuebijing group than that in the Sivelestat sodium injection group and ALI/ARDS model group [52.4% (11/21) vs. 28.6% (6/21), 14.3% (3/21)], and survival rate at the end of experiment was higher in the Sivelestat sodium injection group than that in the ALI/ARDS model group, but the differences were not statistically significant (P > 0.05). In addition, weight and weight growth rate in the Xuebijing injection group were higher than the Sivelestat sodium group at the end of the experiment [weight (g): 217.1±6.4 vs. 207.1±7.0, weight growth rate: (-0.9±2.8)% vs. (-4.3±3.5)%], there were no significant difference between the two groups (both P > 0.05). Lung histopathology in the ALI/ARDS model group revealed high level of inflammatory exudate and inflammatory cells infiltrated in the alveoli of rats, along with damage of local alveolar epithelial cell and alveolar structure. However, these histological changes were improved in the Xuebijing injection group and in the Sivelestat sodium group. Xuebijing injection can alleviate ALI/ARDS-induced lung injury and systemic damage and improve the survival of rats by inhibiting inflammation. The protective effect of Xuebijing injection is essentially consistent with that of Sivelestat sodium.

Acute respiratory distress syndrome due to sepsis caused by Bacteroides ovatus after acute appendicectomy

BackgroundAppendicectomy is generally a minimally invasive surgery, after which postoperative complications such as acute respiratory distress syndrome (ARDS) are rare. We describe a case of ARDS due to sepsis caused by Bacteroides ovatus after appendicectomy.Case presentationA man in his 60 s presented to our hospital with a chief complaint of right lower quadrant abdominal pain. He was diagnosed with acute appendicitis and underwent emergency laparoscopic appendicectomy. Cefmetazole was administered as a perioperative antibacterial drug. Postoperatively, the abdominal findings improved. However, on postoperative day three, bloody sputum and respiratory distress were observed. We performed thoracoabdominal computed tomography (CT) and observed bilateral pleural effusion and mottled frosted glass shadows extending to both lung fields. ARDS was diagnosed. We treated the patient with steroids and sivelestat sodium and switched the antibacterial drug to meropenem. The patient’s general condition improved. After the patient was treated, Bacteroides ovatus was isolated from preoperative blood culture, which was resistant to cefmetazole.ConclusionsWe encountered a case in which ARDS due to sepsis was caused by Bacteroides ovatus after acute appendicectomy. Blood culture to isolate the causative organism and determine its antimicrobial sensitivity after commencement of empiric antibiotics is important even in common diseases, such as acute appendicitis.

Acute respiratory distress syndrome due to inhalation of acryloyl chloride

BackgroundAcryloyl chloride is a highly toxic volatile liquid that can cause pulmonary edema. However, no sufficient treatment reports have been published to date. Here, we report a case of acute respiratory distress syndrome (ARDS) caused by acryloyl chloride inhalation.Case presentationThe patient was a 36‐year‐old man with accidental exposure to acryloyl chloride. The patient had dyspnea and wet cough, with approximately 88% percutaneous oxygen saturation at room air. He was diagnosed with ARDS and admitted to the intensive care unit. Initially, he was treated with a high‐flow nasal cannula and sivelestat sodium. However, due to the possibility of delayed exacerbation, the patient was switched to methylprednisolone. Oxygenation gradually improved, and the patient was discharged on the day 8 of hospitalization.ConclusionWe report the case of a patient who developed ARDS with delayed exacerbation after the inhalation of acryloyl chloride, which was treated without endotracheal intubation.