Study on pathogenesis of idiopathic interstitial pneumonia : Analysis of Hermansky-Pudlak syndrome as a model.

1)本文对Hermansky-Pudlak综合征小鼠模型ep小鼠的肺组织进行了光镜和超微结构观察。在光镜下，ep小鼠肺的II型肺泡细胞在4周龄后显示泡沫状肿胀/变性。超微结构上，巨大的板层体出现在第二型肺细胞在8天的年龄，此后增加的大小和数量。这一改变（GLBD）与Hermansky-Pudlak综合征（HPSIP）患者间质性肺炎（HPSIP）的肺改变几乎一致，提示ep小鼠是阐明HPSIP发病机制的良好小鼠模型。2）小鼠口服胺碘酮400 mg/kg/次后，肺组织病理学改变，3）制备了兔抗HPS 1基因1.5kb cDNA羧基端23个氨基酸残基的多克隆抗体。使用该抗体（HPS 1/ep抗体）和Spritz博士提供的抗HPS 1蛋白的小鼠单克隆抗体（克隆：hHPS 5），以化学方法定位各种组织中的HPS蛋白。肺泡巨噬细胞、肾小管上皮细胞和黑色素瘤细胞胞浆染色较强。HPS 1/ep抗体也染色II型肺细胞。根据病例，受HPSIP影响的肺显示II型肺细胞染色的异质性。ep小鼠肺组织中II型肺泡细胞内的细胞质空泡边缘轮廓呈强染色，提示缺陷型HPS蛋白功能障碍可能是GLBD的原因。

1)The lung tissue of ep mice, a mouse model of Hermansky-Pudlak syndrome, was studied light microscopically and ultrastructurally. Type II pneumocytes of the ep mouse lung showed foamy swelling/degeneration after the age of 4 weeks old at the light microscopic level. Ultrastructurally, giant lamellar bodies appeared within the type II pneumocytes at the age of 8 days, and thereafter increased in size and number. This change (GLBD) was almost identical to that of the lung affected by interstitial pneumonia in patients with Hermansky-Pudlak syndrome (HPSIP), suggesting the ep mouse being a good mouse model for clarifying the pathogenesis of HPSIP.Alveolitis, however, has not been observed in the ep mouse lung so far, and further observation is being conducted.2)The lung tissue of ep mice with oral administration of amiodarone at the dose of 400 mg/kg/day for 6 weeks showed mild alveolitis with mononuclear cell infiltration of the alveolar septa.3)Rabbit polyclonal antibody was raised against a polypeptide corresponding to the 23 amino acid residues encoded at the carboxyl terminal portion of 1.5kb cDNA from the HPS1 gene. This antibody (HPS1/ep antibody) and the mouse monoclonal antibody against the HPS1 protein (clone : hHPS5) supplied by Dr.Spritz were used to to localize the HPS protein in various tissues immunohistochemically. Alveoalr macrophages, renal tubular epithelium and melanoma cells showespecially intense staining in the cytoplasm. HPS1/ep antibody also stained type II pneumocytes. Lungs affected by HPSIP showed heterogeneity in the staining of type II pneumocytes according to the cases. The lungs of ep mice showed intense staining of the marginal contour of cytolasmic vacuoles in the type II pneumocytes, suggesting that dysfunction of the defective HPS protein may be the cause of GLBD.