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

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.

• Authors: Ilonka Rohm, Katja Grün, Linda Marleen Müller, Laura Bäz, Martin Förster, Andrea Schrepper, Daniel Kretzschmar, Rudin Pistulli, Atilla Yilmaz, Reinhard Bauer, Christian Jung, Alexander Berndt, P Christian Schulze, Marcus Franz
• Journal: Clinical hemorheology and microcirculation (Clin Hemorheol Microcirc) Vol. 73 Issue 4 Pg. 497-522 ( 2019) ISSN: 1875-8622 [Electronic] Netherlands
• PMID: 31156142 (Publication Type: Journal Article)

Chemical References

• Endothelin A Receptor Antagonists

Topics

• Animals
• Disease Models, Animal
• Endothelin A Receptor Antagonists (pharmacology, therapeutic use)
• Humans
• Hypertension, Pulmonary (drug therapy, physiopathology)
• Lung (pathology)
• Male
• Rats
• Rats, Sprague-Dawley