Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.
The purposes of this study were to investigate the effect of our recently developed truncated secretory leukoprotease inhibitor (SLPI) on bleomycin (BLM)-induced lung injury and fibrosis in hamsters, which is widely used as a model of interstitial pulmonary fibrosis, and to assess the possible involvement of neutrophil elastase in the pathogenesis of pulmonary fibrosis. The fibrosis model was prepared by administration of BLM (10 mg/kg) intratracheally to hamsters. The truncated SLPI was administered at a dose 5 or 15 mg/kg intraperitoneally twice a day only for 10 d starting from the time of BLM administration. BLM administration resulted in decreases in body weight and survival rate. Elastase activity in the supernatant of bronchoalveolar lavage (BAL) fluids was increased at 3 and 7 d after BLM administration in parallel with the increase in the number of neutrophils in the fluids. Histopathologically, at 14 and 28 d after BLM administration, diffuse thickening and fibrosis of alveolar walls with marked cell infiltration and severe distortion of alveolar structure, including honeycomb lung, were observed to have occurred. In this model, the decreases in body weight and survival rate and the increase in elastase activity were inhibited by the truncated SLPI dose-dependently, and pulmonary fibrosis was significantly ameliorated by the administration of this shortened form of SLPI. These results suggest that neutrophil elastase may be implicated in the pathogenesis of BLM-induced pulmonary fibrosis and that the truncated SLPI might be a promising therapeutic in the treatment of interstitial pulmonary fibrosis.
Mitsuhashi
H
H
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.
Asano
S
S
Nonaka
T
T
Hamamura
I
I
Masuda
K
K
Kiyoki
M
M
D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D006224:Cricetinae; D003627:Data Interpretation, Statistical; D004804:Eosinophils / Q000166:cytology; D005453:Fluorescence; D019272:Leukocyte Elastase / Q000032:analysis; D008168:Lung / Q000473:pathology; D018655:Lymphocyte Count; D008264:Macrophages / Q000166:cytology; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000166:cytology; D010196:Pancreatic Elastase / Q000032:analysis; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000627:therapeutic use*; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors
D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D001761:Bleomycin; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase