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N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

Marie-Camille Chaumais123, Benoît Ranchoux24, David Montani245, Peter Dorfmüller24, Ly Tu24, Florence Lecerf24, Nicolas Raymond24, Christophe Guignabert24, Laura Price6, Gérald Simonneau245, Sylvia Cohen-Kaminsky24, Marc Humbert245 and Frédéric Perros24*

Author Affiliations

1 Univ. Paris-Sud, Faculté de Pharmacie, Châtenay Malabry, France

2 UMRS 999, INSERM et Univ. Paris–Sud, Laboratoire d’Excellence (LabEx) en Recherche sur le Médicament et l’Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France

3 AP-HP, Service de Pharmacie, Département Hospitalo-Universitaire (DHU) Thorax Innovation, Hôpital Antoine Béclère, Clamart, France

4 Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France

5 AP-HP, Centre National de Référence de l’Hypertension Pumonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

6 Department of Pulmonary Hypertension, Royal Brompton Hospital, London, England

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Respiratory Research 2014, 15:65  doi:10.1186/1465-9921-15-65

Published: 14 June 2014

Abstract

Background

The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.

Methods

Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis.

Results

The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001).

Conclusions

Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.

Keywords:
Pulmonary hypertension; Immunomodulation; Inflammation; Right heart function; N-acetylcysteine