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Respiratory Research

, 12:119

First Online: 01 December 2011Received: 14 February 2011Accepted: 09 September 2011

Abstract

BackgroundInvolvement 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.

MethodsWe 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.

ResultsHemodynamic 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.

ConclusionOur 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.

List of abbreviationsO2superoxide

ALKactivin receptor-like kinase

BALTbronchiolar-associated lymphatic tissue

BMPRbone morphogenetic protein receptor

DCdendritic cell

HIFhypoxia inducible factor

HO-1heme oxygenase-1

HPASMChuman pulmonary artery smooth muscle cells

IL-6interleukin-6

IPAHidiopathic pulmonary arterial hypertension

LVleft ventricle

MCT-PEmonocrotaline-pneumonectomy

MCTmonocrotaline

Mn-SODmanganese-superoxidismutase

mPAPmean pulmonary artery pressure

NIHNational Institutes of Health

NOnitric oxide

NOX-4NADPH oxidase-4

OSoxidative stress

PApulmonary artery

PAFBpulmonary artery adventitial fibroblasts

PAHpulmonary arterial hypertension

PBSphosphate buffered saline

PDGFplatelet-derived growth-factor

PEEPpositive end-expiratory pressure

PHpulmonary hypertension

RArheumatoid arthritis

ROSreactive oxygen species

RT-PCRreal time-polymerase chain reaction

RVright ventricle

RVSPright ventricular systolic pressure

Sseptum

SSSjögren-s syndrome

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-12-119 contains supplementary material, which is available to authorized users.

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Autor: Peter Dorfmüller - Marie-Camille Chaumais - Maria Giannakouli - Ingrid Durand-Gasselin - Nicolas Raymond - Elie Fadel - Ola

Fuente: https://link.springer.com/



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