Relationship between neutrophil elastase and acute lung injury in humans

Tamakuma, S; Ogawa, Michio; Aikawa, Naoki; Kubota, Tatsuya; Hirasawa, Hiroyuki; Ishizaka, Akitoshi; Taenaka, Nobuyuki; Hamada, Chikuma; Matsuoka, Shozo; Abiru, Taira

doi:10.1016/j.pupt.2004.05.003

Cited by 161 publications

(137 citation statements)

References 15 publications

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“…In the STRIVE clinical study, however, sivelestat was not effective 10) . This finding was different from tests carried out in Japanese patients with less severe acute lung injury, where the treatment was effective 8) . In contrast, for PMX treatment, significant positive clinical effects were observed during the EUPHAS study carried out in Italy 22) .…”

Section: Effects Of Pmx And/or Sivelestat On Lps-induced Increases Incontrasting

confidence: 92%

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Effects of simultaneous treatment with PMX-DHP and sivelestat on endotoxaemia in conscious guinea pigs

Ishinokami

Nemoto

Ninomiya

et al. 2012

Nihon Kyukyu Igakukai Zasshi

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Using an endotoxaemia model in conscious guinea pigs, we previously reported that polymyxin B immobilized fiber-direct hemoperfusion (PMX-DHP) or administration of sivelestat are effective treatments for sepsis. In the present study, we investigated whether simultaneous treatment with PMX-DHP and sivelestat sodium was more effective than either treatment alone for sepsis. Measurements examined included intestinal paralysis, blood pressure, serum HMGB1 level and survival rate. Colonic motion was monitored continuously by telemetry using a transducer attached to the taenia caecum, while blood pressure was monitored with a carotid artery catheter. The guinea pigs were divided into 4 groups and lipopolysaccharide (LPS) was administered to all animals. The control group received only LPS. The remaining three groups received PMX treatment for 2 hours, sivelestat sodium administration for 2 hours or simultaneous PMX and sivelestat treatment for 2 hours. In the control group, decreased colonic muscle tension and arterial pressure, and increased serum HMGB1 levels were observed and all animals died within 30 hours. In the PMX-DHP treated group, the decreases in colonic tension and arterial pressure were less severe than for the control group and the survival rate was higher than the control group, but serum HMGB1 levels were not significantly different. In the sivelestat group, decreases in colonic tension and arterial pressure were not significantly different with the control group, but serum HMGB1 levels were lower than in the control group. Simultaneous treatment with both PMX-DHP and sivelestat sodium did not exhibit synergistic effects for the treatment of LPS-induced endotoxaemia and mortality. PMX-DHP was effective at treating sepsis induced by administration of a high dose of LPS in guinea pigs, but simultaneous administration of sivelestat sodium did not augment the efficacy of PMX-DHP treatment. (JJAAM. 2012; 23: 12-20)

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Section: Effects Of Pmx And/or Sivelestat On Lps-induced Increases Incontrasting

confidence: 92%

“…Sivelestat sodium hydrate (sivelestat) is a specific NE inhibitor that inhibits increases in vascular permeability mediated by NE. Sivelestat is used to treat acute lung injury (ALI) 8,9) . In Japan, sivelestat has been widely used in clinical practice since 2002.…”

Section: Introductionmentioning

confidence: 99%

Effects of simultaneous treatment with PMX-DHP and sivelestat on endotoxaemia in conscious guinea pigs

Ishinokami

Nemoto

Ninomiya

et al. 2012

Nihon Kyukyu Igakukai Zasshi

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“…Although NE is produced by neutrophils upon activation, and normally serve in host defense against invading microbial pathogens, this cytotoxic product may lead to impairment in tissue repair when released in an unregulated manner 20) . The protective effects of NE inhibitors were first documented in acute lung injury associated with systemic inflammation response, which may occur after infection, surgical intervention, or traumatic or burn injury 21) . Although NE activity was elevated in colon and serum in IBD patients 10,11) , and some have shown the benefits of targeting NE in colitis models 22,23) , the details remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Inhibitor Suppresses Il-17 Based Inflammation of Murine Experimental Colitis

Shioya

Katakura

Ohira

2014

FJMS

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: [Background] Neutrophil elastase (NE) is a proteinase in granulocytes and plays an important role in the pathogenesis of inflammatory disorders. It has been reported that NE activity is elevated in both colonic mucosa and blood in inflammatory bowel disease (IBD) patients, and that it can act as an aggravating factor in IBD. To develop novel therapies for IBD, we examined the effects of an NE inhibitor, Elaspor ® , on murine experimental colitis.[Methods] Acute colitis was induced in BALB/c mice by administration of dextran sulfate sodium (DSS) in drinking water for 7 days. NE inhibitor was administered subcutaneously to mice prior to and during the induction of colitis. Disease activity index (DAI), colonic myeloperoxidase (MPO) activity, luminal NE activity, and mRNA expression in the colon were then investigated.[Results] Subcutaneous administration of NE inhibitor ameliorated the severity of DSS -induced colitis. NE activity was elevated in inflamed colon, and was reduced by NE inhibitor administration. mRNA expression levels of IL -17, a Th17 -based inflammatory factor, was also decreased in the colon of NE inhibitor -administered mice.[Conclusion] These results suggest that NE inhibitor ameliorated colonic inflammation by decreasing both the activity of NE and the effects of cytokine balance. Clinically, NE inhibitor improves injuries associated with systemic inflammatory response syndrome. Similarly, clinical use of this inhibitor would further clarify its usefulness in clinical colonic inflammation.

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“…Sivelestat has been approved for use to treat ALI in humans in Japan (29), although there is no consensus regarding its benefits (30). Tamakuma et al have suggested that sivelestat may function by reducing inflammatory reactions in the injured lung (29). Several studies have reported the relationships between the severity of sepsis, trauma, and burns with SIRS (31).…”

Section: Discussionmentioning

confidence: 99%

Effects of sivelestat on bronchial inflammatory responses after esophagectomy

Yamaguchi

Sugasawa²,

Takeuchi³

et al. 2011

Int J Mol Med

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Abstract. Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

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Relationship between neutrophil elastase and acute lung injury in humans

Cited by 161 publications

References 15 publications

Effects of simultaneous treatment with PMX-DHP and sivelestat on endotoxaemia in conscious guinea pigs

Effects of simultaneous treatment with PMX-DHP and sivelestat on endotoxaemia in conscious guinea pigs

Neutrophil Elastase Inhibitor Suppresses Il-17 Based Inflammation of Murine Experimental Colitis

Effects of sivelestat on bronchial inflammatory responses after esophagectomy

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