title: Inhibition of neutrophil elastase reduces lung injury and bacterial count in hamsters.
abstract: Neutrophil elastase (NE) has been recognized as a double-edge sword as it can be both host-defensive and pro-inflammatory depending on its tissue level and microenvironment. The present study was designed to examine whether inhibition of NE activity by sivelestat, a specific NE inhibitor with low cellular permeability, is beneficial for acute lung injury induced by Streptococcus pneumoniae in hamsters. Intratracheal inoculation of live S. pneumoniae (1.5 x 10(7) CFU/Lung) into hamsters caused acute lung injury characterized by an increase in lung alveolar permeability and leukocytes accumulation in the lungs. These pathophysiological changes, which were associated with elevation of NE activity in the bronchoalveolar lavage fluid (BALF), were transient but remained high 4-22 h post-bacterial inoculation. Intravenous infusion of sivelestat at 3mg/kg/h 0-22 h after bacterial inoculation reduced the increase in NE activity and lung alveolar permeability, as indicated by leakage of pre-injected human serum albumin into BALF, without affecting the number of leukocytes in BALF and lung interstitial tissue. Interestingly, the number of bacteria in BALF and lung interstitial tissue was also reduced by sivelestat to less than 10% of the control values. Furthermore, S. pneumoniae-induced decrease in the level of surfactant protein D (SP-D), a protein that protects against bacterial infection, was preserved by sivelestat treatment with a significant negative correlation between NE activity and SP-D content in BALF. These results suggest that sivelestat is beneficial in acute lung injury associated with lung bacterial infection and that this inhibitor rather decreases infection by preserving host defense system.
authors.affiliation: Minase Research Institute, Discovery Laboratories II, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hagio
authors.forename: Katsuya
authors.initials: K
authors.lastname: Kishikawa
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
mesh_terms: D055371:Acute Lung Injury; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015169:Colony Count, Microbial; D006224:Cricetinae; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000187:drug effects* / Q000378:metabolism; D008647:Mesocricetus; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy / Q000382:microbiology; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D037663:Pulmonary Surfactant-Associated Protein D; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine