背景:特发性肺纤维化(IPF)是一种慢性,导致呼吸衰竭和死亡的进行性纤维化肺病。尽管人们对这种疾病的病因有了更多的了解,仍然无法准确预测个体患者的病程。本研究旨在评估血清细胞因子/趋化因子作为预测IPF患者预后的潜在生物标志物。
方法:采用了使用两个独立队列的多机构前瞻性两阶段发现和验证设计。对于发现分析,来自100名IPF患者和32名健康对照的血清样本使用无偏检查,48种细胞因子/趋化因子的多重免疫测定。在IPF患者和对照组之间比较血清细胞因子/趋化因子值;在IPF患者中评估多重测量与生存时间之间的关联。在验证分析中,我们在另外81例IPF患者的血清样本中检测了发现分析中鉴定的细胞因子/趋化因子,以验证这些细胞因子/趋化因子预测生存期的能力.还进行IPF衍生的肺样品的免疫组织化学评估以确定该新型生物标志物在何处表达。
结果:在发现队列中,与对照组相比,IPF患者血清中的18种细胞因子/趋化因子显着升高。白细胞介素-1受体α(IL-1Rα),白细胞介素-8(IL-8),巨噬细胞炎性蛋白1α(MIP-1α),皮肤T细胞吸引趋化因子(CTACK)与存活相关:IL-1Rα,危险比(HR)=每10个单位1.04,95%置信区间(95%CI)1.01-1.07;IL-8,HR=1.04,95%CI1.01-1.08;MIP-1α,HR=1.19,95%CI1.00-1.36;和CTACK,HR=每100单位1.12,95%CI1.02-1.21。仅对CTACK进行复制分析,因为先前报道其它是间质性肺病的潜在生物标志物。在验证队列中,CTACK与生存率相关:HR=1.14/100单位,95%CI1.01-1.28。免疫组织化学显示CTACK和CC趋化因子受体10(CTACK的配体)在IPF患者的气道和II型肺泡上皮细胞中表达,但在对照组中未表达。
结论:CTACK是IPF的一种新的预后生物标志物。试验登记无(因为没有医疗干预)。
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This
study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients.
METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased,
multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between
multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed.
RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls.
CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF.
Trial registration None (because of no healthcare intervention).