Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • 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

Externe Organisationen

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

OriginalspracheEnglisch
Seiten (von - bis)1382-1396
Seitenumfang15
FachzeitschriftAmerican Journal of Pathology
Jahrgang190
Ausgabenummer7
PublikationsstatusVeröffentlicht - Juli 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.

ASJC Scopus Sachgebiete

Ziele für nachhaltige Entwicklung

Zitieren

Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. / Neubert, Lavinia; Borchert, Paul; Stark, Helge et al.
in: American Journal of Pathology, Jahrgang 190, Nr. 7, 07.2020, S. 1382-1396.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Neubert, L, Borchert, P, Stark, H, Hoefer, A, Vogel-Claussen, J, Warnecke, G, Eubel, H, Kuenzler, P, Kreipe, HH, Hoeper, MM, Kuehnel, M & Jonigk, D 2020, 'Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease', American Journal of Pathology, Jg. 190, Nr. 7, S. 1382-1396. https://doi.org/10.1016/j.ajpath.2020.03.008
Neubert, L., Borchert, P., Stark, H., Hoefer, A., Vogel-Claussen, J., Warnecke, G., Eubel, H., Kuenzler, P., Kreipe, H. H., Hoeper, M. M., Kuehnel, M., & Jonigk, D. (2020). Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. American Journal of Pathology, 190(7), 1382-1396. https://doi.org/10.1016/j.ajpath.2020.03.008
Neubert L, Borchert P, Stark H, Hoefer A, Vogel-Claussen J, Warnecke G et al. Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. American Journal of Pathology. 2020 Jul;190(7):1382-1396. doi: 10.1016/j.ajpath.2020.03.008
Neubert, Lavinia ; Borchert, Paul ; Stark, Helge et al. / Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease. in: American Journal of Pathology. 2020 ; Jahrgang 190, Nr. 7. S. 1382-1396.
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title = "Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease",
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.",
author = "Lavinia Neubert and Paul Borchert and Helge Stark and Anne Hoefer and Jens Vogel-Claussen and Gregor Warnecke and Holger Eubel and Patrick Kuenzler and Kreipe, {Hans Heinrich} and Hoeper, {Marius M.} and Mark Kuehnel and Danny Jonigk",
note = "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). ",
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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.

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DO - 10.1016/j.ajpath.2020.03.008

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AN - SCOPUS:85086357250

VL - 190

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EP - 1396

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 7

ER -

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