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CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats

Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulm...

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Autores principales: Farkas, Daniela, Kraskauskas, Donatas, Drake, Jennifer I., Alhussaini, Aysar A., Kraskauskiene, Vita, Bogaard, Harm J., Cool, Carlyne D., Voelkel, Norbert F., Farkas, Laszlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933653/
https://www.ncbi.nlm.nih.gov/pubmed/24587052
http://dx.doi.org/10.1371/journal.pone.0089810
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author Farkas, Daniela
Kraskauskas, Donatas
Drake, Jennifer I.
Alhussaini, Aysar A.
Kraskauskiene, Vita
Bogaard, Harm J.
Cool, Carlyne D.
Voelkel, Norbert F.
Farkas, Laszlo
author_facet Farkas, Daniela
Kraskauskas, Donatas
Drake, Jennifer I.
Alhussaini, Aysar A.
Kraskauskiene, Vita
Bogaard, Harm J.
Cool, Carlyne D.
Voelkel, Norbert F.
Farkas, Laszlo
author_sort Farkas, Daniela
collection PubMed
description Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit(+) cells and severe pulmonary arterial hypertension. We detected c-kit(+­) cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit(+) α-smooth muscle actin(+) cells and pulmonary arterial muscularization and did not affect c-kit(+) von Willebrand Factor(+) cell numbers. Both c-kit(+) cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit(+) α-smooth muscle actin(+) cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit(+) von Willebrand Factor(+) cells is largely independent of CXC chemokine receptor 4.
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spelling pubmed-39336532014-02-25 CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats Farkas, Daniela Kraskauskas, Donatas Drake, Jennifer I. Alhussaini, Aysar A. Kraskauskiene, Vita Bogaard, Harm J. Cool, Carlyne D. Voelkel, Norbert F. Farkas, Laszlo PLoS One Research Article Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit(+) cells and severe pulmonary arterial hypertension. We detected c-kit(+­) cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit(+) α-smooth muscle actin(+) cells and pulmonary arterial muscularization and did not affect c-kit(+) von Willebrand Factor(+) cell numbers. Both c-kit(+) cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit(+) α-smooth muscle actin(+) cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit(+) von Willebrand Factor(+) cells is largely independent of CXC chemokine receptor 4. Public Library of Science 2014-02-24 /pmc/articles/PMC3933653/ /pubmed/24587052 http://dx.doi.org/10.1371/journal.pone.0089810 Text en © 2014 Farkas et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Farkas, Daniela
Kraskauskas, Donatas
Drake, Jennifer I.
Alhussaini, Aysar A.
Kraskauskiene, Vita
Bogaard, Harm J.
Cool, Carlyne D.
Voelkel, Norbert F.
Farkas, Laszlo
CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title_full CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title_fullStr CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title_full_unstemmed CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title_short CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit(+) Cells in Rats
title_sort cxcr4 inhibition ameliorates severe obliterative pulmonary hypertension and accumulation of c-kit(+) cells in rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933653/
https://www.ncbi.nlm.nih.gov/pubmed/24587052
http://dx.doi.org/10.1371/journal.pone.0089810
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