title: Significant improvement in islet yield and survival with modified ET-Kyoto solution: ET-Kyoto/Neutrophil elastase inhibitor.
abstract: Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Machida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ohmura
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Tanida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Marubashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ito
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005942:Gluconates / Q000494:pharmacology; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D005996:Nitroglycerin / Q000494:pharmacology; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology*; D011897:Random Allocation; D014199:Trehalose / Q000494:pharmacology
chemical_list: D005942:Gluconates; D006895:Hydroxyethyl Starch Derivatives; D053491:Proteinase Inhibitory Proteins, Secretory; C098972:modified ET-Kyoto solution; D003994:Bucladesine; D014199:Trehalose; D005996:Nitroglycerin; D000111:Acetylcysteine