Extensive Phenotyping of Individuals at Risk for Familial Interstitial Pneumonia Reveals Clues to the Pathogenesis of Interstitial Lung Disease
Extensive Phenotyping of Individuals at Risk for Familial Interstitial Pneumonia Reveals Clues to the Pathogenesis of Interstitial Lung Disease
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DOI：
10.1164/rccm.201406-1162oc
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发表时间：
2015-02-15
影响因子：
24.7
通讯作者：
Blackwell, Timothy S.
中科院分区：
文献类型：
--
作者：
Kropski, Jonathan A.;Pritchett, Jason M.;Blackwell, Timothy S.
基本原理：家族性间质性肺炎（FIP）是特发性间质性肺炎的一种遗传形式，其患者的无症状亲属患间质性肺病的风险增加。目的：研究这些高危个体为研究FIP发病机制的早期阶段和建立疾病发作的预测模型提供了独特的机会。75名FIP患者的无症状一级亲属（平均年龄50.8岁）在一项正在进行的队列研究中接受了血液采样和高分辨率胸部计算机断层扫描（HRCT）; 72例患者同意接受支气管肺泡灌洗（BAL）和经支气管活检。27名健康人被用作对照subjects.Measurements和主要结果：11的75例高危受试者（14%）有证据表明，HRCT的间质性变化，而35.2%有异常的经支气管活检。高危个体和对照组BAL中的炎性细胞无差异。高危受试者的无细胞BAL中疱疹病毒DNA增加，肺泡上皮细胞（AEC）中疱疹病毒抗原表达的证据，这与AEC中内质网应激标志物的表达相关。高危人群外周血单个核细胞和AEC端粒长度均短于健康对照组。Muc 5 B rs35705950启动子多态性的次要等位基因频率在高危受试者中增加。几种血浆生物标志物的水平不同的风险主体和对照组之间，并与异常HRCT scanns.Conclusions：肺实质重塑和上皮功能障碍的证据被确定在无症状的个体FIP的风险。总之，这些发现为特发性间质性肺炎的早期发病机制提供了新的见解，并为表征预测临床疾病进展的症状前异常提供了持续的机会。
Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects.Measurements and Main Results: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans.Conclusions: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.