TY - JOUR
AU1 - Kwon, A-H
AU2 - Qiu, Z
AB - Abstract Background During endotoxaemia, neutrophils activated by inflammatory cytokines release reactive oxygen species and neutrophil elastase, resulting in hepatic necrosis and dysfunction. This study investigated the possible mechanism underlying the protective effect of sivelestat, a neutrophil elastase inhibitor, on endotoxin-induced liver injury following partial hepatectomy. Methods Lipopolysaccharide (LPS) was administered intravenously to male Sprague–Dawley rats 48 h after 70 per cent hepatectomy. Sivelestat or normal saline was given intravenously before LPS administration, Results Treatment with sivelestat significantly improved the survival rate. Sivelestat prevented increases in the concentration of serum enzymes and total bilirubin related to liver injury. Levels of inflammatory cytokines in serum and liver tissue were significantly lower in the sivelestat-treated group than in the control group. The degree of neutrophil infiltration, necrosis and apoptosis in the remnant liver was significantly decreased in sivelestat-treated rats. Sivelestat pretreatment inhibited the activation of nuclear factor (NF) κB, caspase 3 and 8 activities, and cytochrome c release. Conclusion Sivelestat prevents LPS-induced liver injury by inhibition of NF-κB activation and apoptosis. Introduction Liver failure associated with postoperative infection may lead to multiple organ failure (MOF) and death1. Although resection of two-thirds of the liver is not fatal, there is increased sensitivity to endotoxin in the period following hepatectomy. In the experimental situation, intravenous injection of a sublethal dose of lipopolysaccharide (LPS) 48 h after surgery is associated with a high mortality rate2. LPS directly activates Kupffer cells to produce inflammatory cytokines3. These cytokines, which are induced by activation of the transcription factor nuclear factor (NF) κB, participate in the development of endotoxaemia and liver injury, leading to MOF, individually or as part of a network4,5. The activation of NF-κB in Kupffer cells is a key event. During endotoxaemia and sepsis, hepatic microvascular dysfunction is effected by leukocyte–endothelial interaction, reduced sinusoidal perfusion and altered phagocytic function of Kupffer cells6. Primed neutrophils release inflammatory mediators including reactive oxygen intermediates and neutrophil elastase7. Excessive release of neutrophil elastase degrades the basement membrane and other extracellular matrix components to cause severe tissue damage through endothelial cell injury8. Sivelestat (ONO-5046; N-[2-(4-[2,2-dimethylpropionyloxy]phenylsulphonyl-amino)benzoyl] amino acetic acid; Ono Pharmaceuticals, Osaka, Japan) is a low molecular weight synthetic inhibitor of neutrophil elastase in various species9. Sivelestat has been shown to attenuate various types of tissue injury, including endotoxin-induced lung injury10, ischaemic and endotoxin-induced liver injury11, aspiration pneumonia12, acute lung injury13 and haemorrhagic shock14. It is known to modulate the production of proinflammatory cytokines contributing to hepatic microcirculatory dysfunction15. The purpose of this study was to investigate the possible mechanism underlying the protective action of sivelestat on endotoxin-induced liver injury following experimental partial hepatectomy. Methods Male Sprague–Dawley rats (250–300 g) (Simizu, Kyoto, Japan) were kept at a controlled temperature under a 12-h light–dark cycle, with free access to food and water. Rats were anaesthetized with ether before undergoing 70 per cent hepatectomy. Forty-eight hours after surgery, 1·5 mg/kg bodyweight LPS (Sigma, St Louis, Missouri, USA) was injected into the penile vein. Sivelestat (0·1, 1·0, 5·0 or 10 mg/kg) or normal saline was administered intravenously to ten animals per group 30 min before LPS injection to determine the effect of dose on survival. The survival rate was monitored over the next 14 days at 12-h intervals. Animals were killed by sodium pentobarbital overdose (300 mg/kg i.p.), then blood samples and livers were obtained at the times indicated. All experimental animals used in this study were treated according to guidelines set by the Animal Care and Use Committee of Kansai Medical University Animal Centre. Biochemical measurements Blood and tissue samples for biochemical analysis were obtained at 1, 3, 6 and 9 h after LPS injection. Serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), and total bilirubin levels were measured using an autoanalyser (model 7170; Hitachi High-technologies, Tokyo, Japan). Serum was stored at − 80 °C until use for cytokine determination. Remnant liver tissue, which was perfused with cold saline via the portal vein, was homogenized in four volumes of cell homogenizing buffer (50 mmol/l Tris-hydrochloric acid, pH 7·4, containing 10 mmol/l EDTA, 1 mmol/l phenylmethylsulphonyl fluoride, 100 µmol/l nafamostat mesilate (Torii Pharmaceutical, Tokyo, Japan) and 200 units/ml trasylol) and centrifuged at 27 000g for 20 min. The supernatant was stored at − 80 °C until use. Levels of tumour necrosis factor (TNF) α, interleukin (IL) 1β, IL-12, interferon (IFN) γ (Biosource International, Camarillo, California, USA) and cytokine-induced neutrophil chemoattractant (CINC) 1 (Immuno-Biological Laboratories, Gunma, Japan) in serum and tissue were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. Histopathology and detection of apoptosis Excised liver specimens were fixed in buffered 10 per cent formalin, embedded in paraffin, cut into 3-µm sections, and stained with haematoxylin and eosin. The extent of liver necrosis and hepatocyte damage was estimated at five levels of depth in individual livers. The degree of necrosis was evaluated by use of a scoring system: 0, negative; 1, one focus or less per field (10× objective); 2, two to four foci per field; 3, five to ten foci per field; and 4, more than ten foci per field. Neutrophil infiltration was evaluated by staining using the naphthol AS-D chloroacetate esterase technique5. The number of neutrophils in 50 randomly selected high-power fields was counted under light microscopy (magnification × 100). Histological evaluations were performed on blinded samples by one surgeon. Apoptotic bodies were detected by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labelling (TUNEL), using an in situ apoptosis detection kit (Takara Shuzo, Shiga, Japan). TUNEL-positive cells were counted in 15 randomly selected high-power fields distributed over at least three independent sections. The apoptosis index was calculated as the number of TUNEL-positive cells expressed as a percentage of the total number of hepatocytes. Electrophoretic mobility shift assay An electrophoretic mobility shift assay for NF-κB was performed16. Briefly, livers were homogenized and centrifuged. The nuclear pellet was resuspended in extraction buffer and the supernatant used as the nuclear fraction. A NF-κB oligonucleotide probe (Promega, Madison, Wisconsin, USA) was labelled with [γ-32P]ATP using T4 polynucleotide kinase. The nuclear extract (4 µg) was incubated with reaction buffer and the labelled probe for 20 min. The products were then electrophoresed on a 4·8 per cent polyacrylamide gel in high ionic strength buffer. Dried gels were analysed by autoradiography. The specificity of the binding reaction was determined by competition reactions using an excess of unlabelled oligonucleotide or by supershift using antibodies against p65 and p50 (Santa Cruz Biotechnology, Santa Cruz, California, USA). Measurement of caspases and cytochrome c in subcellular fractions Cytosolic (S100) fractions were prepared from liver frozen at − 80 °C. Liver sections (0·2 g) were homogenized with a Dounce homogenizer in 1·8 ml ice-cold tissue homogenizing buffer. Unlysed cells and nuclei were removed by centrifugation at 750g for 10 min. The supernatant was centrifuged at 10 000g for 25 min to produce a supernatant containing the S100 fraction. The supernatant was centrifuged for 1 h at 100 000g and the final supernatant represented the S100 fraction. Caspase activity was determined using a colorimetric protease assay kit (Bio Vision, Mountain View, California, USA) (n = 5 animals in each group). S100 fractions containing 200 µg protein were incubated with 200 µmol/l chromogenic substrate for caspase 8 (N-acetyl-Ile-Glu-Thr-Asp-p-nitroanilide; IETD-pNA) or caspase 3 (N-acetyl-Asp-Glu-Val-Asp-p-nitroanilide; DEVD-pNA) at 37 °C for 1 h. Absorbances were measured at 405 nm. Caspase activity was normalized with respect to the absorbance of the normal control (animals without LPS treatment). Cytochrome c released into the cytosolic fraction was measured using a commercial ELISA kit (MBL, Nagoya, Japan) (n = 5 in each group). Standards and 200 µg protein from each S100 fraction were assayed using a one-step sandwich ELISA with an affinity-purified cytochrome c polyclonal antibody and a peroxidase-conjugated cytochrome c polyclonal antibody. Optical density was measured at 450 nm. Statistical analysis Data are expressed as mean(s.e.m.). Comparisons among multiple groups were performed using one-way ANOVA, followed by Bonferroni's post hoc test when variances across groups were equal or by Dunnett's T3 post hoc test when variances were not equal. Differences in survival were measured by the log rank test. P < 0·050 was considered statistically significant. Results Survival Survival was studied following a single intravenous administration of sivelestat after hepatectomy but 30 min before LPS injection. Rats in the control group began to die at 9 h and eight of the ten rats died within 24 h after LPS injection. Sivelestat pretreatment 30 min before LPS administration increased the survival rate in a dose-dependent manner. Two of ten rats treated with 0·1 mg/kg sivelestat died within 24 h and the remaining eight were still alive after 14 days (P < 0·010 versus saline control). None of the animals given 1·0, 5·0 or 10 mg/kg sivelestat died over the 14 days (P < 0·001 versus control). Therefore, a dose of 1·0 mg/kg was used in subsequent experiments. Biochemical variables LPS increased serum levels of AST, ALT, LDH and total bilirubin in partially hepatectomized rats. Sivelestat at 1·0 mg/kg significantly inhibited increases in these markers at 3–9 h after LPS injection, indicating that it attenuated the cellular damage that occurred as a result of hepatic injury by LPS (Fig. 1). Fig. 1 Open in new tabDownload slide Effect of sivelestat pretreatment on levels of a aspartate aminotransferase (AST), b alanine aminotransferase (ALT), c lactate dehydrogenase (LDH) and d total bilirubin. Sivelestat (1·0 mg/kg) or normal saline was injected 30 min before lipopolysaccharide (LPS) administration, some 48 h after partial hepatectomy. Serum samples were obtained 6 h after LPS injection. Values are mean (s.e.m.) (n = 5–7). *P < 0·050 versus saline (one-way ANOVA) Neutrophil infiltration, necrosis and apoptosis in the liver The number of infiltrating neutrophils in the liver increased after LPS injection and was significantly reduced by sivelestat at 3 and 6 h (Fig. 2a). Focal hepatocyte necrosis with associated severe neutrophil and lymphocyte infiltration was prominent in the midzone and periportal regions in LPS-treated rats after hepatectomy. The hepatic necrosis score increased with time after LPS injection, and sivelestat inhibited the increase at 9 h (Fig. 2b). It also significantly inhibited increases in apoptosis, detected by TUNEL staining of the liver, at 6 and 9 h (Fig. 2c). LPS had no significant effects on neutrophil infiltration, necrosis and apoptosis in the sham group. Fig. 2 Open in new tabDownload slide Effect of sivelestat on: a neutrophil infiltration, b necrosis and c apoptosis in the liver. Rats given a single intravenous injection of sivelestat (1·0 mg/kg) or saline were subjected to lipopolysaccharide (LPS) injection 48 h after sham or partial hepatectomy operation; another group received neither LPS nor sivelestat. HPF, high-power fields; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labelling. Values are mean (s.e.m.) (n = 5–7 for hepatectomy and n = 5 for sham operation). *P < 0·050, †P < 0·010 versus LPS + saline (one-way ANOVA) Serum and liver tissue cytokines LPS increased serum levels of TNF-α, CINC-1 and INF-γ in sham-operated rats, but to a lesser extent than in hepatectomized rats. Administration of 1·0 mg/kg sivelestat inhibited increases in these cytokines in the sham-operated group (Fig. 3a–d). In partially hepatectomized rats, sivelestat significantly prevented increases in serum TNF-α levels at 1 and 3 h after LPS injection (Fig. 3e). Serum IL-1β and CINC-1 levels reached a peak 3 h after LPS injection and sivelestat significantly inhibited these increases (Fig. 3f, g). Serum INF-γ levels reached a peak 6 h after LPS injection and sivelestat prevented this increase (Fig. 3h). Fig. 3 Open in new tabDownload slide Effect of sivelestat on serum levels of a, e tumour necrosis factor (TNF) α, b, f interleukin (IL) 1β, c, g cytokine-induced neutrophil chemoattractant (CINC) 1 and d, h interferon (IFN) γ. Rats given a single intravenous injection of sivelestat (1·0 mg/kg) or saline were subjected to lipopolysaccharide (LPS) injection 48 h after sham or partial hepatectomy operation; another group received neither LPS nor sivelestat. Values are mean (s.e.m.) (n = 5–7 for hepatectomy and n = 5 for sham operation). *P < 0·050, †P < 0·010 versus LPS + Saline (one-way ANOVA) To determine whether the increase in serum cytokines resulted from an increase in synthesis and/or secretion in the remnant liver, levels of cytokines were measured in the liver. LPS increased levels of TNF-α, IL-1β, INF-γ and CINC-1 in partially hepatectomized rats. Administration of sivelestat significantly prevented increases in liver tissue TNF-α levels at 1 h after LPS injection. Liver INF-γ levels were significantly lower in the sivelestat group than in the control group at 6 h after LPS injection and CINC-1 levels were lower at 9 h. Sivelestat inhibited the LPS-induced increase in hepatic IL-1β levels, but there were no significant differences (Fig. 4). Fig. 4 Open in new tabDownload slide Effect of sivelestat on liver tissue a tumour necrosis factor (TNF) α, b interleukin (IL) 1β, c cytokine-induced neutrophil chemoattractant (CINC) 1 and d interferon (IFN) γ. Rats given a single intravenous injection of sivelestat (1·0 mg/kg) or saline were subjected to lipopolysaccharide (LPS) injection 48 h after partial hepatectomy. Values are mean (s.e.m.) (n = 5–7). *P < 0·050 versus saline (one-way ANOVA) Activation of transcription nuclear factor κB Recent evidence indicates that NF-κB is involved in transcriptional activation of a variety of inflammatory genes, including those encoding TNF-α, IL-1β and CINC-1. Maximum activation of NF-κB was detected 1 h after LPS administration. Sivelestat pretreatment greatly attenuated the activation of NF-κB. The maximum inhibitory effect of sivelestat on NF-κB activation occurred at 3 h after LPS administration (Fig. 5a, b). In a supershift assay the NF-κB band was decreased and supershifted by p50 and p65 antibodies, demonstrating that NF-κB is composed of a heterodimer of p50 and p65 in rats with or without sivelestat pretreatment (Fig. 5c). Fig. 5 Open in new tabDownload slide Effect of sivelestat on activation of nuclear factor (NF)-κB in liver. Rats given a single intravenous injection of sivelestat (1·0 mg/kg) or saline were subjected to lipopolysaccharide (LPS) injection 48 h after partial hepatectomy. a Nuclear extracts from livers were used for electrophoretic mobility shift assay. Times indicated are after LPS injection. b NF-κB activity was quantified by densitometry and normalized with respect to the level of NF-κB activation in the extract from an LPS-treated control rat at 1 h on the same blot. Values are mean (s.e.m.) NF-κB activity (n = 5 per group per time point). *P < 0·050 (one-way ANOVA). c Representative supershift assay of liver nuclear extracts using p50 and p65 antibodies. Time after LPS injection was 1 h. The specificity of the band was assessed using a competitor (250-fold) Caspase activity and cytochrome c release To confirm the apoptosis of hepatocytes and the antiapoptotic action of sivelestat in LPS-induced liver failure after partial hepatectomy, caspase 3 and 8 activities were measured 1, 3, 6 and 9 h after LPS injection with or without sivelestat pretreatment. Caspase 3 and 8 activities began to increase at 3 h, and were markedly increased at 6 and 9 h, after LPS injection in the livers of LPS-treated rats. Increases at 6 and 9 h after LPS injection were significantly inhibited in rats pretreated with sivelestat (Fig. 6a, b). Cytochrome c release was increased at 6 and 9 h after LPS injection, and sivelestat significantly attenuated this increase (Fig. 6c). Fig. 6 Open in new tabDownload slide Effect of sivelestat on: a caspase 8 activity, b caspase 3 activity and c cytochrome c release in the cytosolic fraction from liver extracts. After a single intravenous injection of sivelestat or saline rats were subjected to lipopolysaccharide (LPS) injection 48 h after partial hepatectomy. OD, optical density. Values are mean (s.e.m.) (n = 5 for each group per time point). *P < 0·050, †P < 0·010 versus saline (one-way ANOVA) Discussion Patients under surgical stress commonly show signs of acute-phase responses17. These changes are related closely to the induction of cytokines18, and the quantity of cytokines induced might be a determinant of the magnitude of the surgical stress19. Endotoxaemia is one of the complications of extended liver resection and a cause of postoperative death20. Inflammatory cytokines and nitric oxide are induced in endotoxaemia after liver resection5,21. Intravenous administration of LPS 48–74 h after partial hepatectomy is considered to be a model of sepsis after extended liver resection4. The present experimental model induced increases in serum levels of AST and LDH, and broad haemorrhagic necrosis in the remnant liver. Sivelestat significantly suppressed this liver damage and improved the survival rate. In septic conditions, TNF-α is the initial and most important cytokine, because it causes the production of IFN-γ, IL-6 and IL-12, and promotes neutrophil priming. The primed neutrophils adhering to the vessel walls release reactive oxygen metabolites and neutrophil elastase, resulting in hepatic microcirculatory dysfunction6,22. Human neutrophil injury of microvascular endothelial cells is enhanced by small amounts of LPS and may be mediated predominantly by the action of neutrophil elastase23. Sivelestat inhibited the production of TNF-α from peritoneal macrophages in rats with caerulein-induced pancreatitis followed by a septic challenge with LPS24. It also inhibited the production of TNF-α, IL-1β and IL-6 released from isolated human monocytes stimulated with endotoxin25. Thus, sivelestat may protect endothelial cells, not only by inactivating the extracellular elastase secreted by neutrophils, but also by acting directly on neutrophils and suppressing the production and secretion of activated elastase26. Neutralization of TNF activity attenuated the release of other mediators during endotoxaemia and decreased liver injury in LPS-treated rats6,27. Activated Kupffer cells have a vast potential for TNF-α production in the liver. In the present study, serum TNF-α levels peaked 1 h after the administration of LPS, followed by increases in other inflammatory cytokines such as IL-1β, IFN-γ and IL-6. IL-1β, which are released from Kupffer cells in the liver following LPS stimulation, acted to induce CINC-1. An increase in CINC-1 has been shown to induce neutrophil infiltration into the liver in sepsis5,28. In the present study, sivelestat significantly blocked increases in these cytokines as well as neutrophil infiltration into the liver. Hepatic upregulation of toll-like receptor (TLR) 4 after hepatectomy causes hypersensitivity to endotoxaemia and leads to significant hepatic dysfunction29. TLR-4 is expressed on Kupffer cells, macrophages and dendritic cells30,31. The activation of NF-κB in macrophages (Kupffer cells) by LPS, through the CD14-dependent downstream receptor TLR-4, coordinates the induction of many genes encoding inflammatory mediators, leading to the synthesis and release of proinflammatory cytokines such as TNF-α32. The upregulated expression of TNF-α leads to a further inflammatory cascade, resulting in macrophage inflammatory protein-2 expression and significant neutrophil accumulation. Activated neutrophils release reactive oxygen species and neutrophil elastase, resulting in hepatic necrosis and dysfunction33. In sepsis, neutrophil-derived elastase may result in further increased chemokine production and increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback for the inflammatory response34. In the present study, activation of NF-κB reached maximal levels 1 h after LPS injection and then declined gradually, consistent with changes in the time course of TNF-α levels in serum and liver after LPS administration. Positive staining for NF-κB has apparently been demonstrated in Kupffer cells rather than in hepatocytes in LPS-treated mice35,36. In the present study, the activation of NF-κB in the liver was suppressed by sivelestat, so it is possible that sivelestat reduced the production of inflammatory cytokines by prevention of the activation of NF-κB in Kupffer cells. TNF-α directly activates caspase 8-dependent apoptotic signals by binding to the TNF-α receptor on the surface of hepatocytes, after which caspase 8 triggers the activation of caspase 3, a downstream cysteine proteinase in multiple apoptosis signal pathways that is critical for the programming of apoptosis37. Bcl-2 and Bcl-xL are located in the outer membranes of mitochondria. Members of the Bcl-2 family prevent the release of cytochrome c from mitochondria, thereby blocking transduction of apoptotic signals downstream of caspase 838 and upstream of caspase 339. In the present experimental model, treatment with sivelestat significantly inhibited the release of cytochrome c, and activation of caspase 8 and 3 after the administration of LPS. Possible pathways involved in the protective effect of sivelestat are illustrated in Fig. 7. Fig. 7 Open in new tabDownload slide Possible mechanism underlying the protective action of sivelestat on endotoxin-induced liver injury following partial hepatectomy. Sivelestat inhibits the activation of nuclear factor (NF) κB which, in turn, leads to a reduction in inflammatory cytokines and promotes Bcl-xL expression, which blocks intracellular apoptotic signals. Sivelestat also inhibits neutrophil elastase, resulting in less tissue injury. LPS, lipopolysaccharide (endotoxin); LBP, LPS-binding protein; TLR, toll-like receptor; TNF, tumour necrosis factor; IL, interleukin This study has shown that sivelestat inhibits the activation of NF-κB, which in turn leads to a reduction in inflammatory cytokines such as TNF-α, and blocks intracellular apoptotic signals. Acknowledgements The authors thank Yoshiko Uemura and Tadayoshi Okumura for helpful advice regarding the pathology scoring system and electrophoretic mobility shift assay for NF-κB. 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TI - Neutrophil elastase inhibitor prevents endotoxin-induced liver injury following experimental partial hepatectomy
JF - British Journal of Surgery
DO - 10.1002/bjs.5625
DA - 2007-04-19
UR - https://www.deepdyve.com/lp/oxford-university-press/neutrophil-elastase-inhibitor-prevents-endotoxin-induced-liver-injury-03docVyvEg
SP - 609
EP - 619
VL - 94
IS - 5
DP - DeepDyve
ER -