Mitsuhashi H, Asano S, Nonaka T, Hamamura I, Masuda K, Kiyoki M
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.
Am J Respir Crit Care Med. 1996 Jan;153(1):369-74. doi: 10.1164/ajrccm.153.1.8542145.
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.
本研究的目的是调查我们最近开发的截短型分泌性白细胞蛋白酶抑制剂（SLPI）对博来霉素（BLM）诱导的仓鼠肺损伤和纤维化的影响（仓鼠广泛用作间质性肺纤维化模型），并评估中性粒细胞弹性蛋白酶在肺纤维化发病机制中的可能作用。通过向仓鼠气管内注射BLM（10 mg/kg）制备纤维化模型。从注射BLM时开始，仅在10天内每天两次腹腔注射剂量为5或15 mg/kg的截短型SLPI。注射BLM导致体重和存活率下降。BLM注射后3天和7天，支气管肺泡灌洗（BAL）液上清液中的弹性蛋白酶活性增加，同时液体中中性粒细胞数量增加。组织病理学上，在BLM注射后14天和28天，观察到肺泡壁弥漫性增厚和纤维化，伴有明显的细胞浸润和肺泡结构严重扭曲，包括蜂窝肺。在该模型中，截短型SLPI剂量依赖性地抑制了体重和存活率的下降以及弹性蛋白酶活性的增加，并且通过给予这种缩短形式的SLPI显著改善了肺纤维化。这些结果表明，中性粒细胞弹性蛋白酶可能与BLM诱导的肺纤维化发病机制有关，并且截短型SLPI可能是治疗间质性肺纤维化的一种有前景的疗法。
