Cellular inflammation in pulmonary hypertension: Detailed analysis of lung and right ventricular tissue, circulating immune cells and effects of a dual endothelin receptor antagonist

Article type: Research Article

Authors: Rohm, Ilonka^a | Grün, Katja^a | Müller, Linda Marleen^a | Bäz, Laura^a | Förster, Martin^a | Schrepper, Andrea^b | Kretzschmar, Daniel^a | Pistulli, Rudin^a | Yilmaz, Atilla^c | Bauer, Reinhard^d | Jung, Christian^e | Berndt, Alexander^f | Schulze, P. Christian^a | Franz, Marcus^{a; *}

Affiliations: [a] Department of Internal Medicine I, Division of Cardiology, Angiology, Pneumology, and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany | [b] Department of Cardiothoracic Surgery, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany | [c] Department of Internal Medicine II, Division of Cardiology, Elisabeth Klinikum Schmalkalden, Schmalkalden, Germany | [d] Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany | [e] Department of Internal Medicine, Division of Cardiology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany | [f] Institute of Pathology, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany

Correspondence: [*] Corresponding author: Marcus Franz, M.D. University Hospital Jena, Friedrich Schiller University Jena Department of Internal Medicine I, Division of Cardiology Am Klinikum 1 D-07747 Jena, Germany. Tel.: +49 0 3641 9324127; Fax: +49 0 3641 9324102; E-mail: marcus.franz@med.uni-jena.de.

Abstract: Growing evidence suggests that inflammation is crucially involved in the pathogenesis of pulmonary hypertension (PH) and consecutive right heart failure. The present study analyzed the inflammatory response in lung and right ventricle in a rat model of PH and evaluated the effects of the dual endothelin receptor antagonist (ERA) Macitentan. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in Sprague-Dawley rats (PH, n = 10) and compared to healthy controls (CON, n = 10) as well as monocrotalin-induced, macitentan-treated rats (THER, n = 10). Detection of Dendritic cells (DCs), regulatory T cells (Tregs) and others as well as RT-PCR based inflammatory gene expression analysis were performed. Circulating DCs and Tregs were quantified by flow cytometry in the rat model and in PH patients (n = 70) compared to controls (n = 52). Inflammatory cells were increased in lung and right ventricular tissue, whereas DCs and Tregs were decreased in blood. Expression of 17 genes in the lung and 20 genes in the right ventricle were relevantly (>2.0 fold) regulated in the PH group. These effects were, at least in part, attenuated in response to Macitentan treatment. In humans as well as rats, immune cells showed significant correlations to clinical, echocardiographic, and haemodynamic parameters. PH is accompanied by a distinct inflammatory response in lung and right but not left ventricular tissue attenuated by Macitentan. Correlations of circulating DCs as well as tissue resident immune cells with parameters reflecting right ventricular function raise the idea of both, promising biomarkers and novel treatment strategies.

Keywords: pulmonary hypertension, right heart failure, inflammation, biomarker, dual endothelin receptor antagonist

DOI: 10.3233/CH-180529

Journal: Clinical Hemorheology and Microcirculation, vol. 73, no. 4, pp. 497-522, 2019