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

1)对Hermansky-Pudlak综合征小鼠模型ep小鼠肺组织进行光镜和超微结构研究。4周龄后ep小鼠肺ⅱ型肺细胞在光镜下表现为泡沫状肿胀/变性。在超微结构上，8日龄时，II型肺细胞内出现巨大的板层体，此后大小和数量增加。这种变化（GLBD）与Hermansky-Pudlak综合征（HPSIP）患者肺间质性肺炎的变化几乎相同，提示ep小鼠是阐明HPSIP发病机制的良好小鼠模型。然而，到目前为止，在ep小鼠肺中未观察到肺泡炎，正在进行进一步的观察。2)口服胺碘酮（400 mg/kg/d） 6周后，ep小鼠肺组织出现轻度肺泡炎，肺泡隔有单核细胞浸润。3)兔多克隆抗体针对HPS1基因1.5kb cDNA羧基末端编码的23个氨基酸残基的多肽。该抗体（HPS1/ep抗体）和spritz博士提供的小鼠抗HPS1蛋白单克隆抗体（克隆：hHPS5）通过免疫组化方法在不同组织中定位HPS1蛋白。肺泡巨噬细胞、肾小管上皮和黑色素瘤细胞的细胞质染色尤其强烈。HPS1/ep抗体也可染色II型肺细胞。经HPSIP感染的肺在II型肺细胞染色上表现出不同的异质性。ep小鼠肺ⅱ型肺细胞胞浆泡边缘轮廓呈强烈染色，提示缺陷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.