Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease

verfasst von

Lavinia Neubert, Paul Borchert, Helge Stark, Anne Hoefer, Jens Vogel-Claussen, Gregor Warnecke, Holger Eubel, Patrick Kuenzler, Hans Heinrich Kreipe, Marius M. Hoeper, Mark Kuehnel, Danny Jonigk

Abstract

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.

Organisationseinheit(en)

Abteilung Pflanzenmolekularbiologie und Pflanzenproteomik

Externe Organisation(en)

Medizinische Hochschule Hannover (MHH)
Biomedical Research in Endstage & Obstructive Lung Disease (BREATH)

Typ

Artikel

Journal

American Journal of Pathology

Band

190

Seiten

1382-1396

Anzahl der Seiten

15

ISSN

0002-9440

Publikationsdatum

07.2020

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Pathologie und Forensische Medizin

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1016/j.ajpath.2020.03.008 (Zugang: Offen)