Inflammatory response and cathepsins in silica-exposed Hermansky-Pudlak syndrome model pale ear mice
Inflammatory response and cathepsins in silica-exposed Hermansky-Pudlak syndrome model pale ear mice
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DOI：
10.1111/j.1440-1827.2004.01626.x
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发表时间：
2004-05-01
影响因子：
2.2
通讯作者：
Fukuchi, Y
中科院分区：
文献类型：
--
作者：
Yoshioka, Y;Kumasaka, T;Fukuchi, Y
Hermansky-Pudlak综合征（HPS）是一种遗传性疾病，涉及细胞内细胞器的分选过程，如网状内皮细胞的溶酶体。已知白耳（ep）小鼠具有HPS 1基因突变，这在HPS和肺纤维化患者中可见。由于在ep小鼠中没有自发观察到肺纤维化，我们假设外部刺激是其发展的遗传易感性所必需的。以二氧化硅为外刺激物诱导小鼠肺泡巨噬细胞介导的炎症反应，观察肺组织病理学变化及溶胶原酶组织蛋白酶L和B的生化分析。用二氧化硅处理诱导了以下结果：激活的巨噬细胞的持续积累;二氧化硅从肺泡腔中的清除延迟;以及肺泡组织中胶原纤维的增加，这在ep小鼠中用三色染色显示。比较支气管肺泡灌洗液细胞之间的幼稚ep和对照组小鼠显示：酶活性降低，但增加的抗原水平的组织蛋白酶L和B，导致活性与抗原的比例显着降低;增加蜡样沉积和溶酶体中的组织蛋白酶L抗原;和没有异常形式的组织蛋白酶被检测到。二氧化硅滴注后，组织蛋白酶L在ep小鼠中的活性增加，但活性与抗原的比率仍显着低。二氧化硅诱导的这些现象表明，外部刺激导致HPS 1基因突变的动物模型或人类的纤维化。
Hermansky-Pudlak syndrome (HPS) is a hereditary disorder involving the sorting processes of intracellular organelles such as lysosomes of reticuloendothelial cells. Pale ear (ep) mouse is known to have the HPS1 gene mutation, which is seen in patients with HPS and pulmonary fibrosis. As pulmonary fibrosis is not spontaneously observed in ep mice, we hypothesized that external stimuli are necessary for the genetic predisposition of its development. We used silica as the external stimulus to induce the alveolar macrophage-mediated inflammatory response and evaluated the pathological changes of the lung and biochemical analysis of collagenolytic lysosomal enzymes cathepsins L and B in ep mice. Treatment with silica induced the following: persistent accumulation of activated macrophages; delayed clearance of silica from alveolar spaces; and increased collagen fibers in alveolar tissues, which were shown with trichrome staining in ep mice. The comparison of bronchoalveolar lavage cells between the naive ep and control mice revealed: decreased enzymatic activities but increased antigenic levels of cathepsins L and B, resulting in significantly lower ratios of activity to antigen; increased ceroid deposits and cathepsin L antigens in lysosomes; and no abnormal forms of cathepsins were detected. After silica instillation, activities of cathepsin L in the ep mice increased but ratios of activity to antigen were still significantly low. These phenomena induced by silica suggest that external stimuli bring forth fibrogenesis in the animal models or humans that have HPS1 gene mutation.