特发性肺纤维化的加速变体：临床行为和基因表达模式。

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of "rapid" and "slow" progressors with IPF. METHODS AND FINDINGS: 26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238+/-98% versus 123+/-29% (p<0.05) and 30+/-17% (p<0.01)]. CONCLUSIONS/SIGNIFICANCE: A subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

背景：特发性肺纤维化（IPF）的特点是呼吸困难或咳嗽逐渐发作。然而，有一部分患者的症状持续时间短，疾病迅速进展至终末期。在这项研究中，我们评估了具有 IPF 的“快速”和“缓慢”进展者的临床和分子特征。

方法和发现：研究了 26 例症状出现前<6 个月[快速进展者]和 88 例症状出现前>24 个月[缓慢进展者]的患者。采用 Kaplan-Meier 法和比例风险模型分析生存情况。在一部分患者中测量了肺微阵列和组织蛋白。两组间在年龄、生理损害和支气管肺泡灌洗（BAL）细胞特征方面无差异。快速进展者组中男性（OR=6.5；CI：1.4-29.5；p=0.006）和吸烟者（OR=3.04；CI：1.1-8.3；p=0.04）更多。快速进展者从症状开始的生存时间显著缩短（HR=9.0；CI：4.48-18.3；p<0.0001），从诊断开始的生存时间也有缩短的趋势（HR=1.5；CI：0.81-2.87；p=0.18）。我们鉴定了 437 个差异表达基因。快速进展者的肺过度表达参与形态发生、氧化应激、迁移/增殖的基因和来自成纤维细胞/平滑肌细胞的基因。通过免疫组织化学验证了两个基因（腺苷-2B 受体和 Prominin-1/CD133）的过表达，并通过肺泡上皮细胞表达。快速进展者的 BAL 显示活性基质金属蛋白酶-9增加了>2 倍，并且与缓慢进展者和对照组相比，诱导的成纤维细胞迁移更多[238+/-98%比 123+/-29%（p<0.05）和 30+/-17%（p<0.01）]。

结论/意义：特发性肺纤维化患者的一个亚组，主要是吸烟男性，表现出加速的临床病程，其基因表达模式与进展较慢和生存时间较长的患者不同。这些发现突出了特发性肺纤维化进展的可变性，并且可能部分解释了在特发性肺纤维化患者治疗干预研究中获得显著和可重复结果的困难。