title: In vivo efficacy of KRP-109, a novel elastase inhibitor, in a murine model of severe pneumococcal pneumonia.
abstract: KRP-109 is a novel specific inhibitor of neutrophil elastase (NE). Various studies suggest that NE inhibitors reduce lung injury associated with systemic inflammatory response syndrome (SIRS). In this study, the efficacy of KRP-109 was examined using a murine model of severe pneumonia induced by Streptococcus pneumoniae (S. pneumoniae). Female mice (CBA/J, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumoniae (ATCC49619 strain, 2.5 × 10(8) CFU/mouse). KRP-109 (30 or 50 mg/kg) or physiological saline as a control was administered intraperitoneally every 8 h beginning at 8 h after inoculation, and survival rate was evaluated over 7 days. Histopathological and bacteriological analyses of the lung, and bronchoalveolar lavage were performed at 48 h post-infection. The mice treated with KRP-109 (KRP-109 mice) tended to have higher survival rate than those given saline. The lung tissues of the KRP-109 mice had few neutrophils in the alveolar walls and less inflammation. Furthermore, KRP-109 decreased significantly total cell and neutrophil counts, and cytokine levels (interleukin 1β and macrophage inflammatory protein 2) in bronchoalveolar lavage fluid. Viable bacterial numbers in lung were not influenced by treatment of KRP-109. The present results indicate that KRP-109 reduces lung inflammation in a murine model, and that KRP-109 may be useful for the treatment of patients with severe pneumonia.
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Nobuko
authors.initials: N
authors.lastname: Araki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Morinaga
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Shimeru
authors.initials: S
authors.lastname: Kamihira
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D048588:Benzoxazines; C570830:KRP-109; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase