Adduri Raju S R, Cai Kai, Velasco-Alzate Karen, Vasireddy Ravikiran, Miller Jeffrey W, de Frías Sergio Poli, de Frías Fernando Poli, Horimasu Yasushi, Iwamoto Hiroshi, Hattori Noboru, Zhang Yingze, Gibson Kevin F, Pal Anoop K, Chen Zhe, Nicastro Daniela, Li Li, Cherian Sujith, Sholl Lynette M, Shetty Sreerama, Ndetan Harrison, Maeda Anthony H, Ferretto Maria A Planchart, Hunninghake Gary M, Schwartz David A, Kass Daniel J, Rosas Ivan O, Konduru Nagarjun V
Department of Cellular and Molecular Biology University of Texas Health Science Center at Tyler Tyler Texas USA.
Departments of Cell Biology and Biophysics University of Texas Southwestern Medical Center Dallas Texas USA.
J Extracell Biol. 2023 Jul 13;2(7):e98. doi: 10.1002/jex2.98. eCollection 2023 Jul.
High-resolution computed tomography (HRCT) imaging is critical for diagnostic evaluation of Idiopathic Pulmonary Fibrosis (IPF). However, several other interstitial lung diseases (ILDs) often exhibit radiologic pattern similar to IPF on HRCT making the diagnosis of the disease difficult. Therefore, biomarkers that distinguish IPF from other ILDs can be a valuable aid in diagnosis. Using mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in patients diagnosed with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects. A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. The five-protein signature derived from mass spectrometry data showed an area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from healthy subjects, respectively. Stepwise backwards elimination yielded a model with 3 and 2 proteins for discriminating IPF from other ILDs and healthy subjects, respectively, without compromising diagnostic accuracy. In summary, we discovered and validated EV protein biomarkers for differential diagnosis of IPF in independent cohorts. Interestingly, the biomarker panel could also distinguish IPF and healthy subjects with high accuracy. The biomarkers need to be evaluated in large prospective cohorts to establish their clinical utility.
高分辨率计算机断层扫描（HRCT）成像对于特发性肺纤维化（IPF）的诊断评估至关重要。然而，其他几种间质性肺疾病（ILDs）在HRCT上常表现出与IPF相似的放射学模式，使得该疾病的诊断变得困难。因此，能够区分IPF与其他ILDs的生物标志物在诊断中可能是一种有价值的辅助手段。我们使用质谱法对诊断为IPF、慢性过敏性肺炎、非特异性间质性肺炎的患者以及健康受试者的血浆细胞外囊泡（EVs）进行了蛋白质组学分析。通过套索回归确定了一个五蛋白特征，并在独立队列中使用酶联免疫吸附测定（ELISA）进行了验证。从质谱数据得出的五蛋白特征在区分IPF与其他ILDs以及与健康受试者时，受试者工作特征曲线下面积分别为0.915（95%置信区间：0.819 - 1.011）和0.958（95%置信区间：0.882 - 1.034）。逐步向后消除法分别产生了一个用于区分IPF与其他ILDs以及与健康受试者的含3种和2种蛋白质的模型，且不影响诊断准确性。总之，我们在独立队列中发现并验证了用于IPF鉴别诊断的EV蛋白生物标志物。有趣的是，该生物标志物组还能高精度地区分IPF和健康受试者。这些生物标志物需要在大型前瞻性队列中进行评估以确定其临床效用。
