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的肺组织进行了光镜和超微结构观察。光镜下可见4周龄后EP小鼠肺泡型肺泡细胞肿胀/变性。超微结构显示，8日龄时，II型肺泡细胞内出现巨型板层小体，以后体积增大，数目增多。这种改变(GLBD)与Hermansky-Pudlak综合征(HPSIP)患者间质性肺炎(HPSIP)所影响的肺几乎相同，表明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，EP小鼠的肺泡炎尚未在EP小鼠肺中观察到。2)经口给予胺碘酮400 mg/kg/d，连续6周的EP小鼠肺组织表现为轻度肺泡炎，肺泡间隔有单核细胞浸润。3)针对HPS1基因1.5kb cDNA羧基末端23个氨基酸残基编码的多肽，制备兔多克隆抗体。用此抗体(HPS1/EP抗体)和Spritz博士提供的小鼠抗HPS1蛋白的单抗(克隆号：hHPS5)，用免疫组织化学方法对HPS蛋白在不同组织中进行定位。肺泡巨噬细胞、肾小管上皮细胞和黑色素瘤细胞胞浆内染色特别强。HPS1/EP抗体也对II型肺泡细胞进行染色。受HPSIP影响的肺组织中的II型肺泡细胞染色呈异质性。EP组小鼠肺组织中II型肺泡细胞胞浆空泡边缘染色较深，提示HPS蛋白缺陷可能是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.