Human neutrophil elastase (HNE) is a protease that participates in tissue injuries of emphysema, rheumatoid arthritis, and septic shock. Sivelestat is a potent, selective, intravenously active HNE inhibitor with an IC50 value of 44±3nM and a Ki value of 200±20nM. It also inhibited leukocyte elastase obtained from rabbits, rats, hamsters, and mice with IC50 values of 36±1, 19±1, 37±4, and 49±5nM, respectively. Sivelestat inhibited porcine pancreas elastase with an IC50 value of 5.6±0.2μM. Intratracheal administration of sivelestat dose-dependently suppressed lung hemorrhage in hamsters with an ID50 value of 82μg/kg. In Guinea pigs, intravenous administration of sivelestat significantly and dose-dependently suppressed HNE-induced increase in skin capillary permeability with an ID50 value of 9.6mg/kg[3]. In rats, intravenous injection of sivelestat at a dosage of 10mg/kg significantly ameliorated lung injury induced by hemorrhagic shock followed by resuscitation[4].
Sivelestat/西维来司他 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human umbilical vein endothelial cells (HUVECs)
20 µM
12 hours
Sivelestat reversed NET-induced endothelial damage and inflammatory responses.
Biomaterials. 2020 Apr;238:119836.
Mouse peritoneal exudate cells (PECs) macrophages
0.5 µg/mL
16 hours
To evaluate the effect of NE on the expression of inflammatory cytokines and CXC chemokines. Results showed that the expression of all examined genes was significantly increased in NE-treated macrophages.
Int J Mol Sci. 2023 Apr 25;24(9):7845.
Rat intestinal epithelial cells
100 µM
24 hours
To investigate the effect of Sivelestat on ZO-1 expression, results showed Sivelestat attenuated NE-induced ZO-1 reduction
Front Pharmacol. 2022 Apr 4;13:838688.
Human neutrophils
10 µM
4 hours
Sivelestat significantly inhibited the release of extracellular DNA and neutrophil elastase from PMA-activated neutrophils, indicating effective inhibition of NET formation.
Biomaterials. 2020 Apr;238:119836.
Primary CD34+ MDS cells
300 µg/ml
72 hours
Inhibited HMGB1 protein expression, reduced cell expansion and colony-forming capacity
Clin Cancer Res. 2019 Jul 1;25(13):4155-4167.
MDS-L cells
300 µg/ml
72 hours
Inhibited HMGB1 protein expression, reduced cell expansion and colony-forming capacity
Clin Cancer Res. 2019 Jul 1;25(13):4155-4167.
Sivelestat/西维来司他 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Liver ischemia-reperfusion injury model
Intravenous injection
0.2 mg/kg per hour
From anesthesia induction to postoperative day 1
Sivelestat mitigated liver ischemia-reperfusion injury by inhibiting neutrophil elastase activity, evidenced by reduced serum ALT and AST levels
Sivelestat significantly attenuated the acute lung injury caused by fat embolism, including the increases in lung weight/body weight ratio, lung weight gain, exhaled NO, protein concentration in bronchoalveolar lavage fluid, pulmonary arterial pressure, and microvascular permeability. Additionally, Sivelestat reduced the activities of neutrophil elastase, myeloperoxidase, malondialdehyde, and phospholipase A2, and decreased the levels of nitrate/nitrite, methyl guanidine, tumor necrosis factor α, and interleukin-1β.
J Biomed Sci. 2012 Jan 5;19(1):3
Sprague-Dawley rats
Hindlimb ischemia-reperfusion injury model
Intravenous injection or intramuscular injection
15 or 60 mg/kg/d
Once daily for 7 days
Sivelestat at 15 mg/kg bw/d improved hindlimb perfusion, promoted angiogenesis, reduced muscle fibrosis, and enhanced motor function by eliminating NETs; while local injection at 60 mg/kg bw/d had adverse effects on tissue repair
J Inflamm Res. 2023 Feb 21;16:707-721
Mice
Acute liver failure model
Intraperitoneal injection
150 mg/kg
Single dose, 24 hours before ALF induction
Sivelestat pretreatment significantly attenuated D-GalN/LPS-induced liver necrosis and hepatocellular damage, reduced serum ALT and AST levels, and decreased neutrophil infiltration in the liver.
Sivelestat significantly reduced bacterial loads in AAT-KO mice after S. pneumoniae infection and protected alveolar collectin SP-D from NE-dependent degradation.
JCI Insight. 2021 Feb 8;6(3):e140816
BALB/c mice
APAP-induced acute liver injury model
Intraperitoneal injection
200 mg/kg
Single dose at 30 min, 3 h, or 5 h after APAP challenge
To evaluate the protective effect of Sivelestat on APAP-induced acute liver injury. Results showed that Sivelestat treatment significantly improved survival, reduced serum transaminase elevation and hepatic necrosis, and decreased intrahepatic neutrophil infiltration and NOS-II expression.
Int J Mol Sci. 2023 Apr 25;24(9):7845.
C57BL/6 mice
Partial inferior vena cava ligation (pIVCL) model
Subcutaneous injection
30 mg/kg
Three times a week for six weeks
To investigate the effect of Sivelestat on pIVCL-induced portal hypertension, results showed that Sivelestat reduced portal pressure and fibrin formation.
Gastroenterology. 2019 Jul;157(1):193-209.e9
NSG mice
MDS-L cell transplantation model
Intraperitoneal injection
5 mg/kg
Once daily for 7 days
Reduced MDS-L cell engraftment in the bone marrow, inhibited MDS cell expansion
Clin Cancer Res. 2019 Jul 1;25(13):4155-4167.
BALB/c mice
LPS-induced endotoxic shock model
Intraperitoneal injection
50 mg/kg
Single dose, observed for 18 hours
Nanoparticle-mediated delivery of sivelestat effectively inhibited NET formation, decreased the clinical signs of lung injury, reduced NE and other proinflammatory cytokines in serum, and rescued animals against endotoxic shock.
Biomaterials. 2020 Apr;238:119836.
Mice
FFD-induced MASH model
Intraperitoneal injection
50 mg/kg
Three times a week, for 6 weeks
Sivelestat significantly reduced the MoKC proportion, liver steatosis, inflammation and fibrosis in mice
Exp Mol Med. 2025 Feb;57(2):450-465
C57BL/6J mice
Renal ischemia-reperfusion injury model
Intravenous injection
50 mg/kg
Single dose
Pretreatment with sivelestat significantly reduced renal Neutrophil elastase (NE), serum creatinine, and blood urea nitrogen levels after renal ischemia-reperfusion. Sivelestat also reduced histological damage and cell apoptosis in kidneys following ischemia-reperfusion injury (IRI). Additionally, sivelestat administration decreased the mRNA expression levels of interleukin 6 (IL-6), Macrophage inflammatory protein-2 (MIP-2), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-α in the kidneys during IRI. The kidney tissues of the SI group showed significantly reduced TLR4, Myd88, and NF-κB p-p65 protein expression levels compared to the I group (all P<0.05).
Drug Des Devel Ther. 2024 Oct 5;18:4449-4458
Sprague-Dawley (SD) rats
Cecal ligation and puncture (CLP)-induced sepsis model
Intraperitoneal injection
50 mg/kg
Single dose, observed for 24 hours
To evaluate the effects of Sivelestat on survival rate, gut microbiome, and metabolite profiles in septic rats. Results showed that Sivelestat significantly improved the survival rate of septic rats (80% vs 50%) and ameliorated gut microbiota composition and metabolite profiles.
Front Cell Infect Microbiol. 2022 Mar 15;12:818391
ApoE-/- mice
High-fat high-cholesterol diet-induced atherosclerosis model
Intraperitoneal injection
50 mg/kg/day
Once daily for 8 weeks
To investigate the effect of Sivelestat on atherosclerosis, results showed Sivelestat attenuated atherosclerotic phenotypes, including decreasing toxic lipid accumulation, vascular monocyte infiltration, and inflammatory cytokines
Front Pharmacol. 2022 Apr 4;13:838688.
Sprague-Dawley rats
Cecal ligation and puncture (CLP)-induced sepsis model
Intraperitoneal injection
50 or 100 mg/kg
Immediately after surgery, observed up to 108 hours
To evaluate the protective effects of Sivelestat on sepsis-related acute kidney injury. Results showed that Sivelestat improved the survival rate of septic rats, restored mean arterial pressure and glomerular filtration rate, inhibited the increase in serum blood urea nitrogen and neutrophil gelatinase-associated lipocalin levels, and reduced the production of inflammatory mediators and macrophage infiltration.
搜索
