PATHOGENESIS AND THERAPY OF PULMONARY FIBROSIS

常染色体隐性遗传的赫-普二氏综合征 (HPS)特征是眼皮肤白化病， 储存池缺陷，蜡样脂褐素的溶酶体积累， 肺纤维化，并在第五个十年死亡。HPS发生 在世界范围内，但其发病率最高的是波多黎各人（PR）。我们 研究了26名PR和19名非PR个体，3-35岁， HPS。23例PR患者中21例出现16 bp重复， 17名非PR患者中，HPS基因的分子分析 被执行。16例PR成人（平均年龄34岁）与 7例非PR成人（平均年龄32岁），证明PR成人 用力肺活量较低（82+/-25%vs111 +/-19%，p < 0.05）。另外，16例成人中有9例16-bp重复， 10例无16-bp重复的成年人的DLCO值</- 预测值的80%（Fisher双尾，p=0.0039）。即使一个 非重复成年人的DLCO降低，风险的比值比 肺纤维化的16 bp复制阳性个体， 约12.8（95%置信区间，1.1-300）。10个16 bp 复制阳性PR个体，具有不同程度的 通过支气管肺泡灌洗评价肺纤维化。 16-bp的BAL中细胞数增加2-3倍 复制阳性的HPS比正常人的HPS高。的 高分辨率CT纤维化评分 与HPS亚组中的%VC和FEV 1相关 个体（分别为p=0.03和0.04）。这些研究记录了 波多黎各人患肺纤维化的风险增加 在赫曼斯基-普德拉克综合征基因中有16个碱基的重复。 此外，它们区分16-bp复制阳性PR形式 的医保计划，并提供试验计划的基础。 抗纤维化药物在PR患者HPS和显着 限制性疾病

Autosomal recessive Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a platelet storage pool defect, lysosomal accumulation of ceroid lipofuscin, pulmonary fibrosis, and death in the 5th decade. HPS occurs worldwide, but its incidence is highest in Puerto Ricans (PR). We studied 26 PR and 19 non-PR individuals, 3-35 years of age with HPS. A 16-bp duplication was found in 21 of 23 PR patients, and 0 of 17 non-PR patients in whom molecular analysis of the HPS gene was performed. A comparison of 16 PR adults (mean age 34y) with 7 non-PR adults (mean age 32y), demonstrated that the PR adults had lower forced vital capacities (82+/-25% vs 111+/-19%, p < 0.05). In addition, 9 of 16 adults with the 16-bp duplication, but 0 of 10 adults without the 16-bp duplication had DLCO values </- 80% of predicted (Fisher's 2-tailed, p=0.0039). Even if one non-duplication adult had a reduced DLCO, the odds ratio for risk of pulmonary fibrosis in 16-bp duplication-positive individuals is approximately 12.8 (95% confidence interval, 1.1-300). Ten 16-bp duplication-positive PR individuals with various degrees of pulmonary fibrosis were evaluated by bronchoalveolar lavage. There were 2-3 fold more cells in the BAL of 16-bp duplication-positive HPS than in that from normal individuals. The high resolution computerize axial tomography fibrosis score correlated with the %VC and FEV1 in this subset of HPS individuals (p=0.03 and 0.04, respectively). These studies document an increased risk of pulmonary fibrosis in Puerto Rican individuals with a 16-bp duplication in the Hermansky-Pudlak Syndrome gene. Further, they differentiate the 16-bp duplication-positive PR form of HPS from the non-PR form and provide the basis for a trial of anti-fibrotic agents in PR patients with HPS and significant restrictive disease.