Reduction in circulating Endothelin-1 levels by inhaled COPD medications

• Published in: Respiratory medicine Vol. 240; p. 108027
• Main Authors: Sato, Hiroki, Nagano, Tatsuya, Suraya, Ratoe, Hazama, Daisuke, Umezawa, Kanoko, Katsurada, Naoko, Yamamoto, Masatsugu, Tachihara, Motoko, Nishimura, Yoshihiro, Emoto, Noriaki, Kobayashi, Kazuyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2025
• Subjects: Administration, Inhalation; Aged; Animals; Bronchodilator Agents - administration & dosage; Budesonide - administration & dosage; Budesonide - pharmacology; Chronic obstructive pulmonary disease; COPD; Disease Models, Animal; Endothelin; Endothelin-1 - blood; Endothelin-1 - drug effects; Female; Formoterol Fumarate - administration & dosage; Formoterol Fumarate - pharmacology; Humans; Hypertension, Pulmonary - etiology; Male; Mice; Middle Aged; Pulmonary Disease, Chronic Obstructive - blood; Pulmonary Disease, Chronic Obstructive - complications; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - physiopathology; Pulmonary hypertension; Respiratory Function Tests - methods; Tumor Necrosis Factor-alpha; Chronic obstructive pulmonary disease; Endothelin; Pulmonary hypertension; COPD
• ISSN: 0954-6111; 1532-3064; 1532-3064
• DOI: 10.1016/j.rmed.2025.108027

Chronic obstructive pulmonary disease (COPD) can be complicated by pulmonary hypertension (PH), impacting prognosis and quality of life. Endothelin-1 (ET-1) is implicated in PH development and elevated in COPD patients. The impact of COPD treatments on ET-1 and COPD-related PH remains unclear. This study investigated changes in ET-1 levels after administration of inhaled COPD medications and explored underlying mechanisms. Patients underwent pulmonary function tests, COPD Assessment Test, and plasma ET-1 measurement before and 4–12 weeks after treatment initiation. In mice, elastase-induced emphysema was treated with budesonide (BUD), glycopyrronium (GLY), and formoterol (FOR) combinations for 2 weeks. Plasma ET-1 concentration and cytokine expression were analysed. HULEC-5a cells were used to examine ET-1 expression after TNFα stimulation. The study included 33 patients. COPD patients (n = 24) showed higher baseline plasma ET-1 levels compared to controls (n = 9) (2.12 pg/ml vs 1.54 pg/ml, p < 0.001). Plasma ET-1 levels decreased in COPD patients posttreatment (2.12–1.82 pg/ml, p = 0.004), with reductions observed across all disease stages and treatment regimens. Mice showed elevated ET-1 levels and expression of inflammatory cytokines after elastase instillation. BUD/GLY/FOR treatment significantly reduced ET-1 concentration and TNFα expression. Furthermore, TNFα stimulation upregulated ET-1 expression in HULEC-5a cells. In COPD patients conventional treatment decreased ET-1 concentration. In mouse models TNFα expression was suppressed by BUD/GLY/FOR. In HULEC-5a cells, TNFα stimulation exerted an increased ET-1expression. These findings suggest that the suppressive effect of inhaler therapy on ET-1 expression is due to the anti-inflammatory effects of these drugs. •Patients with COPD have an elevated plasma level of ET-1.•Inhaler therapy induces a decrease in plasma ET-1 levels in COPD patients.•ET-1 levels and TNFa expression are elevated in COPD mouse models.•Treatment for COPD mouse models exhibited a decrease in ET-1 levels and TNFα expression.•TNFα stimulation induced expression of ET-1 in endothelial cells.