Institute of Pathology, Hannover Medical School, Hannover, Germany; German Center for Lung Research (DZL), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany.
Institute of Pathology, Hannover Medical School, Hannover, Germany; German Center for Lung Research (DZL), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany.
Am J Pathol. 2020 Jul;190(7):1382-1396. doi: 10.1016/j.ajpath.2020.03.008. Epub 2020 Apr 7.
Pulmonary hypertension and pulmonary vascular remodeling (PVR) are common in many lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences in both the pulmonary arterial and venous compartments, as in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), respectively. Our goal was to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional pulmonary hypertension therapy. Formalin-fixed and paraffin-embedded tissues from fresh explanted human lungs of patients with PVOD (n = 19), PAH (n = 20), idiopathic pulmonary fibrosis (n = 13), and chronic obstructive pulmonary disease (n = 15), were analyzed for inflammation and kinome-related gene regulation. The generated neuronal network differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Further, various alterations were identified regarding the gene expression of explanted lungs with PVR, compared with controls. Specifically, the dysregulation of microtubule-associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases.
肺动脉高压和肺血管重塑（PVR）在许多导致右心室功能障碍和死亡的肺部疾病中很常见。PVR 的差异导致肺动脉和静脉腔在预后上存在显著差异，分别在肺动脉高压（PAH）和肺静脉闭塞性疾病（PVOD）中。我们的目标是确定 PVR 的特定腔室分子特征，考虑到如果采用传统的肺动脉高压治疗，PVOD 发生威胁生命的肺水肿的风险。对来自 PVOD（n = 19）、PAH（n = 20）、特发性肺纤维化（n = 13）和慢性阻塞性肺疾病（n = 15）患者新鲜离体人肺的福尔马林固定和石蜡包埋组织进行了炎症和激酶组相关基因调控分析。所生成的神经元网络在随机选择的验证集中，以 100%的灵敏度和 92%的特异性将 PVOD 与 PAH 样本区分开来，其水平远优于既定的诊断算法。此外，与对照组相比，患有 PVR 的离体肺的基因表达也发生了各种改变。具体而言，微管相关丝氨酸/苏氨酸激酶 2 和蛋白-o-甘露糖激酶 SGK196 在所有疾病组中的失调首次表明它们在肺血管病变中起关键作用。我们的研究结果有望帮助开发针对特定靶点的新干预措施和创新方法，以促进这组难以捉摸的疾病的临床诊断。
