Effect Of Neutrophil Elastase Inhibitor Research Articles

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.

Neutrophil elastase inhibitor suppresses oxidative stress in obese asthmatic rats by activating Keap1/Nrf2 signaling pathway.

The aim of this study was to detect the oxidative stress response in the rat model of obesity, asthma and obese asthma. Meanwhile, we aimed to investigate the inhibitory effect of neutrophil elastase inhibitor (NEI) on cellular oxidative stress in the body and whether it exerted an effect on the oxidative stress response in obese asthma through the Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2 (Keap1/Nrf2) pathway. The obesity and asthma models were established using a total of 70 Sprague-Dawley (SD) rats. All rats were randomly divided into 7 groups. The rats with normal weight were divided into the control (CTR) group (n=10), asthma (ATM) group (n=10) and ATM+NEI group (n=10). Meanwhile, the obese rats were divided into the obesity (OBS) group (n=10), the OBS+NEI group (n=10), the OBS+ATM group (n=10) and the OBS+ATM+NEI group (n=10). After modeling, rats in NEI intervention groups were injected with Sivelestat (5 mg/kg) via the caudal vein twice a day for 1 week. The tests of cough sensitivity to capsaicin and bronchial responsiveness were performed 24 h after the last administration. Lung tissues of rats were collected for hematoxylin-eosin (HE) staining. Meanwhile, the levels of reactive oxygen species (ROS) in heart, lung and kidney tissues were detected via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The activities of reduced glutathione (GSH), glutathione peroxidase (GSH-Px), H2O2 and total superoxide dismutase (T-SOD) in the heart, lung and kidney tissues were detected using the colorimetric method. The mRNA and protein expressions of Keap1 and Nrf2 messenger ribonucleic acid expressions in the heart, lung and kidney tissues were measured via Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting, respectively. NEI significantly improved the symptoms and lung pathology in rats with asthma. The level of ROS in the heart, lung and kidney tissues of the OBS group, ATM group and OBS+ATM group was significantly increased. However, NEI markedly inhibited the level of ROS in rats with asthma. The activities of antioxidant stress-related enzymes (reduced GSH, GSH-Px, H2O2 and SOD) in the heart, lung and kidney tissues of the OBS group, ATM group and OBS+ATM group were significantly decreased. However, NEI markedly promoted the activities of the related antioxidant enzymes in oxidative stress response in asthma rats. Besides, the Keap1/Nrf2 signaling pathway in the heart, lung and kidney tissues of the OBS group, ATM group and OBS+ATM group was significantly inhibited, while NEI activated the Keap1/Nrf2 signaling pathway in rats with asthma. NEI promotes the release of a variety of antioxidant factors, enhances the activity of antioxidant enzymes and improves the symptoms of rats with obese asthma. The possible underlying mechanism may be the activation of the Keap1/Nrf2 signaling pathway.

Effects of neutrophil elastase inhibitor in patients undergoing esophagectomy: a systematic review and meta-analysis.

To evaluate the benefit and safety of sivelestat (a neutrophil elastase inhibitor) administration in patients undergoing esophagectomy. Online databases including PubMed, EMBASE, the Cochrane Library, Web of Knowledge, and Chinese databases (Wanfang database, VIP and CNKI) were searched systematically up to November 2013. Randomized controlled trials and high-quality comparative studies were considered eligible for inclusion. Three reviewers evaluated the methodological quality of the included studies, and Stata 12.0 software was used to analyze the extracted data. The risk ratio (RR) was used to express the effect size of dichotomous outcomes, and mean difference (MD) or standardized mean difference was used to express the effect size of continuous outcomes. Thirteen studies were included in this systematic review and nine studies were included in the meta-analysis. The duration of mechanical ventilation was significantly decreased in the sivelestat group on postoperative day 5 [I (2) = 76.3%, SMD = -1.41, 95%CI: -2.63-(-0.19)]. Sivelestat greatly lowered the incidence of acute lung injury in patients after surgery (I (2) = 0%, RR = 0.27, 95%CI: 0.08-0.93). However, it did not decrease the incidence of pneumonia, intensive care unit stay or postoperative hospital stay, and did not increase the incidence of complications such as anastomotic leakage, recurrent nerve palsy, wound infection, sepsis and catheter-related fever. A neutrophil elastase inhibitor is beneficial in patients undergoing esophagectomy. More high quality, large sample, multi-center and randomized controlled trials are needed to validate this effect.

Neutrophil elastase inhibitor reduces ventilation-induced lung injury via nuclear factor-κB and NF-κB repressing factor in mice.

Mechanical ventilation used in patients with acute lung injury can damage pulmonary epithelial cells through production of inflammatory cytokines, oxygen radicals, and neutrophil infiltration, termed ventilator-induced lung injury. Neutrophil elastase, nuclear factor-κB (NF-κB), and NF-κB repressing factor (NRF) have previously been shown to participate in the regulation of macrophage inflammatory protein-2 (MIP-2) during airway inflammation. However, the mechanisms regulating interactions among mechanical ventilation, neutrophil influx, and NF-κB/NRF remain unclear. Thus, we hypothesized that neutrophil elastase inhibitor attenuated ventilation-induced neutrophil recruitment and MIP-2 production through inhibition of the NF-κB/NRF pathway. Male C57BL/6 mice were exposed to low-tidal-volume (6 mL/kg) or high-tidal-volume (30 mL/kg) mechanical ventilation using room air with or without 2 µg/g NF-κB inhibitor SN50 or 6 µg/g NRF short interfering RNA or 100 µg/g neutrophil elastase inhibitor administration. Nonventilated mice served as a control group. Evan blue dye, lung wet-to-dry weight ratio, free radicals, myeloperoxidase, histopathologic grading of lung tissue, inflammatory cytokines, Western blot of NF-κB and NRF, and gene expression of NRF were measured to establish the extent of lung injury. Neutrophil elastase inhibitor ameliorated high-tidal-volume ventilation-induced lung injury, neutrophil influx, production of MIP-2 and malondialdehyde, activation of NF-κB and NRF, apoptotic epithelial cell death, and disruption of bronchial microstructure in mice. Mechanical stretch-augmented acute lung injury was also attenuated through pharmacological inhibition of NF-κB activity by SN50 and NRF expression by NRF short interfering RNA. Our data suggest that neutrophil elastase inhibitor attenuates high-tidal-volume mechanical ventilation-induced neutrophil influx, oxidative stress, and production of MIP-2, at least partly, through inhibition of NF-κB/NRF pathway. Understanding the protective effects of neutrophil elastase inhibitor associated with the reduction of MIP-2 allow clarification of the pathophysiological mechanisms regulating severe lung inflammation and development of possible therapeutic strategies involved in acute lung injury.

Effects of neutrophil elastase inhibitor on flap survival after venous ischemia

Venous ischemia is more of a threat to tissue viability than is arterial ischemia. The mechanism of injury is complex and involves many factors. Neutrophil activation is thought to be a trigger and final pathway for the tissue injury. We conducted a two-part animal study to examine the effect of neutrophil elastase inhibitor on ischemia–reperfusion injury. In the first experiment, island abdominal skin flaps were elevated in 20 rabbits (ten treated with neutrophil elastase inhibitor and ten not treated), and the pedicle vein was occluded for 6 h in both groups. Survival rates (i.e., flap survival areas) and histologic findings were compared. In the second experiment, thrombus formation was assessed in arterioles and venules injured by reactive oxygen species. Survival of the treated flaps and non-treated flaps was 91 (46–100) and 0 (0–98) %, respectively, and differed significantly (p < 0.002). Histologically, infiltration of neutrophils was observed 12 h after congestion, and severe obstruction of vessels due to thrombi was observed 48 h after congestion in the non-treatment group, but vessels were not obstructed in the treated group. Thrombi in venules contained leukocytes, but those in arterioles did not. Time to stasis in the venules in the treatment group and non-treatment group was 130.5 (96–197) and 93 (62–133) s, respectively (p < 0.01). Neutrophil elastase inhibitor was shown to maintain flap circulation and thus promote flap survival. This agent may slow thrombus formation in venules by acting on neutrophils in the venules.

Effects of Neutrophil Elastase Inhibitor on Progression of Acute Lung Injury After Liver Transplantation

We read with interest the article recently published in Transplantation by Uchida et al. (1) describing protective function of neutrophil elastase (NE) inhibitor in liver ischemia-reperfusion injury. The authors concluded that NE inhibition may represent an effective therapeutic option in liver transplantation (LT). Despite recent advances in surgical techniques and perioperative management, LT has a relatively high in-hospital mortality and morbidity rate (2). In addition to ischemia-reperfusion injury, pulmonary complications including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently occur after LT. If uncontrolled, ALI/ARDS leads to in-hospital death. Therefore, prevention of postoperative ALI/ARDS is important to reduce in- hospital mortality after LT. Pulmonary endothelial barrier disruption plays a critical role in the development of ALI/ARDS. Especially, neutrophils and NE play important roles in endothelial injury and increased vascular permeability, which are the characteristics of ALI/ARDS (3). Pulmonary vascular hyperpermeability, a cause of hypoxemia during the early postoperative course, could be caused by NE released from neutrophils accumulating in the lung (4). Sivelestat (ONO Pharmacol, Osaka, Japan) is a synthetic selective inhibitor of NE (5). In the field of organ transplantation, there have been some reports showing beneficial effects of Sivelestat in lung or liver ischemia-reperfusion injury in experimental animal model (1, 6, 7). However, there has been no clinical study examining its usefulness in LT. In this study, we therefore conducted a prospective, nonrandomized, clinical pilot study to examine the effect of Sivelestat on postoperative ALI in patients undergoing LT. Between April 2007 and May 2008, 62 consecutive adult patients who underwent living donor LT at Kyoto University Hospital were prospectively enrolled in the study. After matching for underlying disease, the patients were nonrandomly assigned to receive a continuous intravenous infusion of 300 mg/kg per day of Sivelestat (Sivelestat group, n=31) dissolved in 50 mL of saline or saline only (control group, n=31) just after admission to the intensive care unit after surgery. The patients in both the groups were treated until the ratio of arterial oxygen tension (PaO2)-to-the fractional concentration of inspired oxygen (FiO2) (PF ratio) was more than 300. Blood samples for arterial blood gas analysis were drawn twice daily throughout the experiment. The duration of systemic inflammatory response syndrome (SIRS) was also measured. The definition for SIRS was in accordance with that of the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference (8). The protocol was approved by the ethical committee of Kyoto University Hospital following the guidelines of the 1975 Declaration of Helsinki. The written informed consent was obtained from each patient before participation in the study. Continuous variables were expressed as the means±SD, or as the median and range, and the differences in continuous variables were analyzed by Student's t test. Comparisons of the categorical or ordinal variables were performed using chi-square test or Fisher exact test where appropriate. A P value less than 0.05 was considered significant. The characteristics of patients including age, gender, underlying disease, Child-Pugh classification, and model for end-stage liver disease score, were not different between the two groups. The decrease in the PF ratio after surgery shown in the control group was prevented in the Sivelestat group (Fig. 1). The PF ratios on the first, second, and third postoperative days (PODs) in the Sivelestat group were significantly higher than those in the control group (POD1, 322±74 vs. 258±90, P=0.002; POD2, 318±106 vs. 224±88, P=0.002; and POD3, 330±91 vs. 214±82, P<0.001), whereas the PF ratio on intensive care unit admission was lower in the Sivelestat group than that in the control group (324±87 vs. 359±90, P=0.160). Moreover, the duration of SIRS was significantly shorter in the Sivelestat group compared with that in the control group (2.3±2.1 days vs. 3.7±3.7 days, P=0.023).FIGURE 1.: The ratio of arterial oxygen tension to the fractional concentration of inspired oxygen (PF ratio) after surgery. The decrease in PF ratio after surgery shown in the control group was prevented in the Sivelestat group. ICU, intensive care unit; POD, postoperative day.This is the first report that shows the preventive effect of Sivelestat against ALI after living donor LT in clinical settings. Several studies suggested that Sivelestat improved ALI partially by inhibiting inflammation or nuclear factor-κB activity (6, 9, 10). Although plasma levels of proinflammatory and antiinflammatory cytokines were not examined in this study, the amelioration of posttransplant ALI might be partially caused by its antiinflammatory effect. Further investigations are thus required to elucidate mechanism of the preventive effect of Sivelestat against ALI. Randomized controlled trials of Sivelestat for posttransplant ALI after LT are needed to confirm this finding. Toshimi Kaido Shinji Uemoto Division of Hepato-Biliary-Pancreatic and Transplant Surgery Department of Surgery Graduate School of Medicine Kyoto University Kyoto, Japan

Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) in the Treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis

Sivelestat is neutrophil elastase inhibitor, which is widely used in Japan for the treatment of acute lung injury. However, the clinical efficacy of the medication has not been convincingly demonstrated. We conducted a systematic review and meta-analysis of randomized controlled trials on sivelestat for the treatment of acute lung injury and acute respiratory distress syndrome. Studies were identified using MEDLINE, EMBASE, Cochrane library, conference proceedings, and references of included studies. Authors were contacted if necessary. ICHUSHI, the Japanese database for medical literature and conference proceedings was also used for the search, since many studies on sivelestat were published in Japanese language and not registered in major databases such as MEDLINE. The primary outcome was mortality within 28-30 days after randomization. Relative risks were pooled with the random effect model. 8 trials were included in the analysis. There was no difference in mortality within 28-30 days after randomization (relative risk 0.95, 95% confidence interval 0.72 to 1.26). Subgroup analysis conducted only on studies conducted in Japan showed the same result (0.59, 0.28 to 1.28). There was no difference in mechanical ventilation days (standardized mean difference -0.43, -1.12 to 0.27), but sivelestat was associated with a better short term PaO(2)/FiO(2) ratio (0.30, 0.05 to 0.56). Heterogeneity was not significant for the main analysis and funnel plot did not suggest publication bias. Sivelestat was not associated with decreased mortality, even when including studies published in Japanese language.

Effects of neutrophil elastase inhibitor on acute experimental colitis in mice

Objective To study the effects of neutrophil elastase (NE) inhibitor (sivelestat) on acute experimental colitis induced by dextran sulfate sodium (DSS) in mice.Methods A total of twenty-six healthy male BALB/C mice were randomly divided into four groups as follows:normal control group(n=6),experimental control group(n=6,treated with phosphate-buffered saline intraperitoneally for 9 days),low-dose group(n=7,treated with sivelestat 50 mg/kg intraperitoneally for 9 days) and high-dose group(n=7,treated with sivelestat 100 mg/kg intraperitoneally for 9 days).Acute experimental colitis model was generated by giving 5% DSS solution.All mice were sacrificed at 10th day to assess the scores of histological injury in colon tissues.The concentration of NE was examined by enzyme-linked immunosorbent assay (ELISA) in both plasma and cultured supernatant of colonic mucosa.The expression of NE in distal colon was analyzed by Western blotting.Results The colonic histological injury score in experimental control group (12.00±2.45) was markedly increased compared with that in normal control group(1.88±0.83,P＜0.0 1).There was a significant difference in scores of colonic histological injury between low-dose group (10.17±1.17) and high-dose group (5.00±1.15,P＜0.05),however,they were both lower than that in experimental control group and higher than that in normal control group (P＜0.05).Compared with normal control group,the concentrations of NE in plasma,and cultured supernatant of colonic mucosa and the expression of NE in distal colon were increased in experimental control group (P＜0.05).And those in low-dose group were higher than those in normal control group (P＜0.05),but were little decreased in comparison with experimental control group (P＞0.05).Whereas those in high-dose group,which showed no significant difference with normal control group (P＞0.05),were significantly decreased compared with experimental control group and low-dose group (P＜0.05).Conclusions Sivelestat,a specific NE inhibitor,may alleviate the DSS-induced experimental colitis,in which high-dose is more effective than low-dose.It suggests that NE may be involved in the pathogenesis of ulcerative colitis. Key words: Colitis; ulcerative; Leukocyte elastase; Diease model; animal

Effects of Neutrophil Elastase Inhibitor on the Reduction of Radiation Pneumonitis

Effects of Neutrophil Elastase Inhibitor on the Reduction of Radiation Pneumonitis

The effect of neutrophil elastase inhibitor on acute tubular necrosis after renal ischemia-reperfusion injury

In renal transplantation, ischemia-reperfusion (I/R) injury is a major cause of renal dysfunction. Activated neutrophils are reported to be closely involved in I/R injury after renal transplantation. Neutrophil elastase, a protease released from activated neutrophils, damages tubular endothelial cells. We investigated the beneficial effect of neutrophil elastase inhibitor (ONO-5046.Na) on renal I/R injury in rats. The study was conducted using 10 male Lewis rats (270-320 g) that were intravenously administered ONO-5046.Na (30 mg/kg before ischemia and after reperfusion) (group A) and control rats (group B) in a 90-min renal warm I/R injury model. Neutrophil elastase expression was analyzed using immunohistochemical staining, and the degree of renal dysfunction was evaluated using H&E staining and blood biochemistry. Neutrophil elastase was detected in tubular endothelial cells. The necrotic area extended to and encompassed nearly all the ischemic kidney within 12 h after reperfusion. The necrotic area and the grade of neutrophil elastase staining were significantly reduced in group A compared to group B. Significant differences in blood urea nitrogen and serum creatinine levels were observed. Survival rates over a 14-day period were examined. No rats survived for more than 4 days in group B. However, 2 of the 10 rats (20%) in group A survived for a 14-day period. To conclude, ONO-5046.Na inhibits neutrophil elastase and reduces acute tubular necrosis. Thus, it is a potent therapeutic agent for the control of renal I/R injury in renal transplantation.

Neutrophil elastase inhibitor, sivelestat sodium hydrate prevents ischemia–reperfusion injury in the rat bladder

In the present study, we evaluated the effect of neutrophil elastase inhibitor, sivelestat sodium hydrate on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamping with a small clip to induce ischemia-reperfusion injury in the bladder. Eight-week-old male Sprague Dawley rats were divided into four groups; sham-operated control rats, 30 min ischemia-60 min reperfusion (IR) rats, and IR rats treated with 15 or 60 mg/kg of sivelestat sodium hydrate. Sixty minutes prior to induction of ischemia, sivelestat sodium hydrate was administrated intraperitoneally. Real-time monitoring of blood flow and nitric oxide (NO) release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. The NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental urinary bladders. Clamping of the abdominal aorta, blood flow was rapidly decreased and NO release was gradually increased. After removing the clip, blood flow was rapidly increased and NO release was gradually returned to the basal level. These movements of blood flow and NO release were inhibited by treatment with sivelestat sodium hydrate in a dose-dependent manner. Both NO2-NO3 and MDA concentrations in the bladder were increased by induction of IR, and NO2-NO3 and MDA concentrations were decreased by treatment with high dose of sivelestat sodium hydrate significantly. Our data indicated that sivelestat sodium hydrate could inhibit increasing NO2-NO3 and MDA concentrations by IR, and it has potentiality protective effects on IR injury in the rat urinary bladder.

Protective Effect of Neutrophil Elastase Inhibitor (FR136706) in Lethal Acute Liver Failure Induced by D-Galactosamine and Lipopolysaccharide in Rats

It has been reported that liver dysfunction with ischemia-reperfusion is improved through selective inhibition of neutrophil elastase (NE) by NE inhibitor. This study was designed to investigate whether NE inhibitor has protective effect in lethal acute liver failure. Rats were treated with D-galactosamine plus lipopolysaccharide (GalN/LPS) to induce acute liver failure. NE inhibitor (FR136706) was administered intravenously before GalN/LPS injection. NE inhibitor increased the survival rate to approximately 80% compared with less than 10% in GalN/LPS-treated rats. NE inhibitor prevented GalN/LPS-induced increase of enzymes and total bilirubin in serum, which are related to liver injury. Histopathological analysis revealed that NE inhibitor decreased the incidence of hepatic apoptosis and neutrophil infiltration in the liver. NE inhibitor inhibited the increased concentration of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6 and interferon-gamma), and chemokines (CINC-1 and MIP-2) in serum or liver caused by GalN/LPS, and enhanced anti-inflammatory cytokine, interleukin-10 concentration. NE inhibitor prevented the activation of the transcription factor, nuclear factor-kappa B, induced by GalN/LPS. NE inhibitor also reduced the induction of inducible nitric oxide synthase mRNA and its protein in GalN/LPS-treated liver, and resulted in a decrease in nitric oxide production. These results indicate that NE inhibitor, FR136706, inhibits the induction of a variety of inflammatory mediators such as cytokines, chemokines, and nitric oxide, in part through the inhibition of nuclear factor-kappa B activation, resulting in the prevention of fulminant liver failure.

Beneficial effect of neutrophil elastase inhibitor on anti‐Thy1.1 nephritis in rats

Neutrophil elastase, one of the proteinases released by neutrophils, plays an important role at the sites of inflammation and was reported to be involved in the pathogenesis of glomerulonephritis. Sivelestat is a selective neutrophil elastase inhibitor used for acute lung injury associated with systemic inflammatory response syndrome. There have been few reports on the effects of sivelestat on renal disease. In male Wistar rats, anti-Thy1.1 nephritis was induced by the injection of anti-Thy1.1 antibody. The rats were divided into four groups: nephritic rats treated with low- (group A) and high-dose sivelestat (group B), those not treated with sivelestat (group C) and control rats (group D). Urine samples were obtained every day during the experiment. The rats were killed on day 6 in order to obtain the blood plasma and kidneys. Measurement of urine protein levels, blood biochemical values and histological examination of the kidneys were carried out. Increased levels of proteinuria were observed in the nephritic rats (groups A, B and C) compared with group D. The proteinuria level was significantly suppressed by sivelestat in groups A and B in a dose-dependent fashion compared with group C. The light microscopy revealed an increased glomerular cell count in group C, which was significantly suppressed in group B. In the electron microscopic study, sivelestat suppressed the fusion of epithelial foot process, especially in group B. Neutrophil elastase is suggested to be involved in the development of anti-Thy1.1 nephritis, and the neutrophil elastase inhibitor sivelestat reduces the tissue injury of anti-Thy1.1 nephritis in rats.

Effects of Neutrophil Elastase Inhibitor on Progression of Acute Lung Injury Following Esophagectomy

The purpose of this study was to evaluate the effect of sivelestat sodium hydrate, a selective inhibitor of neutrophil elastase in the systemic inflammatory response, pulmonary function, and the postoperative clinical course following esophagectomy. Patients with hypoxia associated with surgical stress in the intensive care unit (ICU) immediately after an esophagectomy were eligible for this study. The degree of hypoxia was calculated according to the ratio of arterial oxygen tension (PaO(2)) to the fractional concentration of inspired oxygen (FiO(2))-PaO(2)/FiO(2). Patients with PaO(2)/FiO(2) < 300 mmHg were enrolled in this study. Seven patients were treated with sivelestat, and 10 were not so treated. The degree of hypoxia, the criteria for systemic inflammatory response syndrome (SIRS), and the postoperative clinical course were compared between the two groups. The postoperative decreases in the PaO(2)/FiO(2) ratio were significantly suppressed in the sivelestat group (p < 0.05, by analysis of variance, or ANOVA). Furthermore, 9 of the 10 control group patients developed SIRS on postoperative day 2, whereas only 2 of 7 of the sivelestat group patients developed SIRS (p < 0.05). The postoperative increases in the heart rate were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The postoperative decreases in the platelet counts were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The duration of mechanical ventilation and the length of ICU stay for the sivelestat group were shorter than that for the control group. We demonstrated that the postoperative decreases in the PaO(2)/FiO(2) ratio following esophagectomy were significantly suppressed in the sivelestat-treated group. This clinical study showed that a neutrophil elastase inhibitor may thus be a potentially useful drug for treating acute lung injury following esophagectomy.

Effect of Neutrophil Elastase Inhibitor on Coagulability in Patients after Radical Esophagectomy

食道癌術後には凝固異常が発症することが知られている。この凝固異常に対しては，現在までステロイドなどさまざまな薬剤投与が試みられてきた。今回われわれは，好中球エラスターゼの特異的阻害剤（シベレスタットナトリウム，以下SN）投与の食道癌術後の凝固能におよぼす影響について検討した。対象は食道癌切除再建を一期的に行った41例で，これら症例を術後SNを投与した21例（SN+群）と，SNを投与しなかった20例（SN-群）に分けた。SN+群でSNを，術直後より0.2mg/kg/hrで術5病日まで持続的に投与した。全例で術直前にメチルプレドニゾロン（500mg）を投与し，術7病日まで血小板数・FBG·FDP·D-Dimer·AT3·TAT·APTT·Protein C・α2PIを経時的に測定した。血小板数・FBG·FDP·D-Dimer·TATの変動には両群に差がなかった。AT3とProtein Cは術2·3病日でSN+群が有意に高値で，α2PIは術3病日でSN+群が有意に高値であった。APTTは，術3病日にSN-群で有意に高かった。食道癌術後管理におけるエラスターゼ阻害剤投与は食道癌術後の凝固異常状態を制御し，早期に回復させることが可能である。

Benefical Effect of Neutrophil Elastase Inhibitor on Renal Warm Ischemia-Reperfusion Injury in the Rat

Renal ischemia-reperfusion (I/R) injury is a significant problem in renal transplantation. Neutrophils play an important role in renal I/R injury. Several reports have demonstrated that neutrophil elastase derived from the activated neutrophils might play an important role in this injury. We investigated the effect of a neutrophil elastase inhibitor in renal I/R injury. Male Lewis rats (270–320 g) were used in the model. The right kidney was harvested and the left renal artery and vein were clamped at laparotomy. The kidney was reperfused after 90 minutes of ischemia. Neutrophil elastase inhibitor (ONO-5046: 30 mg/kg) was delivered intravenously before ischemia and after reperfusion to prevent neutrophil activation. In the nontreatment I/R group, no hosts survived 4 days. However, after treatment with neutrophil elastase inhibitor, 3 of 10 rats in the I/R group, survived more than 7 days. These results demonstrated that treatment with neutrophil elastase inhibitor ameliorated renal I/R injury.

Effects of Neutrophil Elastase Inhibitor on Postoperative Respiratory Management in Patients with Acute Abdomen

Effects of Neutrophil Elastase Inhibitor on Postoperative Respiratory Management in Patients with Acute Abdomen

Protective effects of a selective neutrophil elastase inhibitor (sivelestat) on lipopolysaccharide-induced acute dysfunction of the pulmonary microcirculation

The purpose of this study was to evaluate the effect of a neutrophil elastase inhibitor, sivelestat, on lipopolysaccharide-induced acute lung injury through analysis of hemodynamic changes in the pulmonary microcirculation. Randomized animal study. Medical school laboratory. Twenty-seven Wistar rats (15 rats for microspectroscopic observations, 12 rats for measurements of neutrophil elastase activity and wet-to-dry ratio). Thoracosternotomy was performed on male Wistar rats under continuous anesthesia and mechanical ventilation. Rats were divided into three groups (n = 5 each groups) on the basis of the reagent used: lipopolysaccharide group (100 microg/kg lipopolysaccharide intravenously), sivelestat group (10 mg/kg sivelestat; 100 microg/kg lipopolysaccharide intravenously), and control group (saline only, intravenously). We measured morphologic changes and hemodynamic variables, including tissue blood flow, erythrocyte velocity, erythrocyte count, thickness of interalveolar septa, and leukocyte adhesion in the pulmonary microcirculation, with a video-rate (33 msec/frame) dual-spot microspectroscopy system (DSMSS) and a laser-Doppler flowmeter. Blood-free wet-to-dry ratio and neutrophil elastase activity in bronchoalveolar lavage fluid, serum, and supernatant of lung homogenate were measured in another set of experiments (n = 4 for each group). Sixty minutes after lipopolysaccharide administration, severe thickening of the interalveolar septa was observed in the lipopolysaccharide but not the sivelestat group. In the lipopolysaccharide group, DSMSS measurements of erythrocyte velocity and hemoglobin oxygenation in single capillaries were decreased significantly (vs. control p < .05, vs. sivelestat p < .01), whereas tissue blood flow and erythrocyte velocity measurements from laser-Doppler flowmeter were increased significantly (vs. control p < .05, vs. sivelestat p < .01). The number of adherent leukocytes was increased significantly in the lipopolysaccharide group at 30, 45, and 60 mins after lipopolysaccharide administration (vs. control p < .01, vs. sivelestat p < .05). The number of adherent leukocytes did not increase in the sivelestat group. The wet-to-dry ratio was significantly higher in the lipopolysaccharide group than in control (p < .05) and sivelestat (p < .05) groups. Neutrophil elastase activities in the bronchoalveolar lavage fluid, serum, and lung tissue were all significantly lower in the sivelestat group than in the lipopolysaccharide group (p < .05). Lipopolysaccharide induces leukocyte adhesion in the pulmonary microcirculation, resulting in decreased tissue hemoglobin oxygen and alveolar and interstitial edema. The selective neutrophil elastase inhibitor sivelestat reduces neutrophil elastase activity and attenuates acute changes in the pulmonary microcirculation.

Effects of Neutrophil Elastase Inhibitor in Preventing Lung Injury after Esophagectomy for Esophageal Cancer

Effects of Neutrophil Elastase Inhibitor in Preventing Lung Injury after Esophagectomy for Esophageal Cancer

Effect of Neutrophil Elastase inhibitor, ICI 200,355, on Interleukin-1 Induced acute lung injury in rats

Background: Interleukin-1(IL-1) and neutrophil appear to contribute to the pathogenesis of acute respiratory distress syndrome(ARDS). Elastase, as well as reactive oxygen species released from activated neutrophil, are thought to play pivotal roles in the experimental models of acute lung leak. This study investigated whether ICI 200,355, a synthetic elastase inhibitor, can attenuate acute lung injury induced by IL-1 in rats. Materials and Methods: We intratracheally instilled either saline or IL-1 with and without treatment of ICI 200,355 in rats. Lung lavage neutrophils, lung lavage cytokine-induced neutrophil chemoattractant(CINC) concentration, lung lavage protein concentration, lung myeloperoxidase(MPO) activity and lung leak index were measured at 5 hours of intratracheal treatment. Results: In rats given IL-1 intratracheally, lung lavage neutrophils, lung lavage CINC concentration, lung lavage protein concentration, lung MPO activity and lung leak index were higher. Intratracheal ICI 200,355 administration decreased lung lavage neutrophils, lung MFO activity and lung leak index, respectively, but did not decrease lung lavage CINC concentration. Conclusion: These results suggest that ICI 200,355 decreases lung inflammation and leak without decreasing lung lavage CINC concentration in rats given IL-1 intratracheally.