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Respiratory Research
Published in: Respiratory Research 1/2011

Open Access 01-12-2011 | Research

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Authors: Peter Dorfmüller, Marie-Camille Chaumais, Maria Giannakouli, Ingrid Durand-Gasselin, Nicolas Raymond, Elie Fadel, Olaf Mercier, Frédéric Charlotte, David Montani, Gérald Simonneau, Marc Humbert, Frédéric Perros

Published in: Respiratory Research | Issue 1/2011

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Abstract

Background

Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation.

Methods

We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE).

Results

Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68+/vimentin+ cells.

Conclusion

Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.
Appendix
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Metadata
Title
Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension
Authors
Peter Dorfmüller
Marie-Camille Chaumais
Maria Giannakouli
Ingrid Durand-Gasselin
Nicolas Raymond
Elie Fadel
Olaf Mercier
Frédéric Charlotte
David Montani
Gérald Simonneau
Marc Humbert
Frédéric Perros
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2011
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-12-119

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