title: The effect of plasma-derived activated protein C on leukocyte cell-death and vascular endothelial damage.
abstract: BACKGROUND
  The role of leukocyte and its death in the progression in inflammation attracts attention nowadays. The purpose of this study is to examine the effects of activated protein C (APC) on leucocyte cell death and vascular endothelial damage in sepsis.
  
  
  METHODS
  Wistar rats were infused with lipopolysaccharide (8.0mg/kg) concomitantly with either a low dose (0.5mg/kg), a high dose (5.0mg/kg) of plasma-derived APC or albumin. One and 3hours after the injections, the mesenteric microcirculation was observed by intravital microscopy. The serum levels of nucleosome and High Mobility Group Box 1 (HMGB1) were measured in each group. In another series, cultured leukocyte cell-death in the medium supplemented with serum obtained from each group was examined in vitro.
  
  
  RESULTS
  Microcirculatory disturbance was significantly suppressed in both the high-dose and low-dose groups compared to the control group (P<0.01, 0.05, respectively). The bleeding area was significantly increased in the control and high-dose groups (P<0.05, 0.01, respectively). Serum levels of cell death markers such as nucleosome and HMGB1 were significantly decreased in the treatment groups (P<0.01), and the protective effect was more pronounced in high-dose group. Cell death suppression was most prominent in high-dose group and the formation of neutrophil extracellular traps (NETs) was significantly suppressed in the treatment groups.
  
  
  CONCLUSIONS
  Low-dose plasma-derived APC exerted protective effects on the microcirculation without increasing the risk of bleeding. The protective effect against leukocyte cell death and the suppressive effect on NETs formation of APC might be related to its beneficial effects.
authors: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of MedicineJapan. Electronic address: toshiiba@cf6.so-net.ne.jp.
authors: Toshiaki
authors: T
authors: Iba
authors: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of MedicineJapan. Electronic address: kun@juntendo-urayasu.jp.
authors: Kunihiko
authors: K
authors: Nagakari
mesh_terms: D000818:Animals; D016923:Cell Death; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology*; D007962:Leukocytes / Q000276:immunology / Q000473:pathology*; D008070:Lipopolysaccharides / Q000276:immunology; D008833:Microcirculation; D011486:Protein C / Q000276:immunology* / Q000627:therapeutic use; D017208:Rats, Wistar; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000628:therapy
chemical_list: D008070:Lipopolysaccharides; D011486:Protein C
keywords: High Mobility Group Box 1; Intravital microscope; Microcirculation; Necrosis; Neutrophil extracellular traps; Nucleosome