title: The neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats.
abstract: Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor‑α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury.
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Guofu
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Kaiqiang
authors.initials: K
authors.lastname: Ji
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zang
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D000071068:Lipocalin-2 / Q000097:blood; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000071068:Lipocalin-2; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D019272:Leukocyte Elastase; D005998:Glycine