Details
| Original language | English |
|---|---|
| Pages (from-to) | 1382-1396 |
| Number of pages | 15 |
| Journal | American Journal of Pathology |
| Volume | 190 |
| Issue number | 7 |
| Publication status | Published - Jul 2020 |
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.
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In: American Journal of Pathology, Vol. 190, No. 7, 07.2020, p. 1382-1396.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease
AU - Neubert, Lavinia
AU - Borchert, Paul
AU - Stark, Helge
AU - Hoefer, Anne
AU - Vogel-Claussen, Jens
AU - Warnecke, Gregor
AU - Eubel, Holger
AU - Kuenzler, Patrick
AU - Kreipe, Hans Heinrich
AU - Hoeper, Marius M.
AU - Kuehnel, Mark
AU - Jonigk, Danny
N1 - Funding Information: This project was funded by the CRC 738/3 (Project B9), the Central Innovation Programme for Small and Medium-Sized Enterprises (SMEs) grant ZF4549001CR8 (D.J. and M.K.), the KFO311 (Project Z2) (D.J.), the European Consolidator Grant 771883 [Hanover experimental lung research project (XHaLe)] (D.J.), and the German Center for Lung Research (DZL).
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086357250&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2020.03.008
DO - 10.1016/j.ajpath.2020.03.008
M3 - Article
C2 - 32275906
AN - SCOPUS:85086357250
VL - 190
SP - 1382
EP - 1396
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 7
ER -