The Prostacyclin-Mimetic Cicaprost Inhibits Endogenous Endothelin-1 Release From Human Pulmonary Artery Smooth Muscle Cells

Abstract

Experimental evidence indicates that the potent vasoconstrictor peptide endothelin-1 (ET-1) has a pivotal role in the pathogenesis of both primary (1) and secondary (2) forms of human pulmonary hypertension. Despite this little is known about the control and sites of ET-1 production during these disease processes. In patients with primary pulmonary hypertension (PPH) urinary excretion of prostacyclin metabolites is lowered (3). In the same patient group, prostacyclin (epoprostenol) administered as a continuous intravenous infusion improves pulmonary vascular resistance (4) and mortality (5). The mechanism of this beneficial effect remains unclear. We aimed to compare the ability of human pulmonary artery smooth muscle cells (HPASM) to produce ET-1 under inflammatory conditions with human pulmonary microvascular endothelial cells (HPMVE) under the same conditions. In addition, we assessed a possible interaction between prostacyclin and endogenously pro-duced ET-1 by HPASM in order to identify a potential control mechanism. MATERIALS AND METHODS Cell cultureSpecimens of human pulmonary artery were obtained from patients undergoing pulmonary resection at the Royal Brompton Hospital (London, U.K.). Vessels were cleaned of adventitia, the endothelium removed and cut into 3-4 mm sections. Dulbecco's modified Eagle medium was added to the tissue, supplemented with 15% fetal calf serum (FCS), glutamine, streptomycin, penicillin and non-essential amino acids. HPASM were identified by staining with fluorescein isothiocyanate-(FITC) labelled anti-smooth muscle actin antibody and were used at passage 2-9 (6). HPMVE cells were purchased from Clonetics (San Diego, CA, U.S.A.).Journal of Cardiovascular Pharmacology™ 36 (Suppl. 1):S410-S413

Synergistic Induction of Endothelin-1 by Tumor Necrosis Factor α and Interferon γ Is due to Enhanced NF-κB Binding and Histone Acetylation at Specific κB Sites

“…Vessels were dissected clean from adventitia under sterile conditions, and the endothelium was removed mechanically, cut into 3-4-mm 2 sections, and cultured as previously described (6). Cells between passages 2 and 9 were either seeded onto 96-well plates or tissue culture flasks.…”

“…Although endothelial cells are thought to be the main source of ET-1 release, several groups including our own have shown that ET-1 can be released from the more numerous vascular smooth muscle cells (5)(6)(7)(8)(9)(10). The vascular pathology observed in pulmonary arterial hypertension is propagated by inflammation, and circulating levels of cytokines including tumor necrosis factor ␣ (TNF␣) are elevated in patients with pulmonary arterial hypertension (11)(12)(13)(14)(15).…”

The Significance of Soluble Molecules of Cellular Adhesion, Nitric Oxide Metabolites, and Endothelin-1 and Their Associations as Markers of Progression of Inflammation in COPD

“…Damage to the endothelium and the development of endothelial dysfunction account for the formation of the most significant systemic manifestations (comorbid states) of COPD and mainly result from the excessive secretion of endothelin-1 (ET-1) by the cells of the vascular endothelium [8]. ET-1 belongs to a class of regulatory peptides and plays a key role in processes involved in fibrogenesis of vascular walls and bronchi, in the induction and maintenance of vasoconstriction and bronchoconstriction, as well as in the steady progression of chronic inflammation [9]. ET-1 level is increased in the blood serum in diseases caused by smoking, endothelial dysfunction and pulmonary hypertension [10][11][12].…”

“…The functional ability of ET-1 is its pleiotropy. It is known that excessive accumulation of this vasoactive peptide in response to the realization of an endothelial dysfunction causes initiation of fibrogenesis in the lungs, induction of vaso-and bronchoconstriction [9,13,31,32]. It is probable that the increased concentration of ET-1 in the blood is one of the most unfavorable factors influencing the processes of the remodeling of bronchopulmonary tissue in conditions of the activation and progression of chronic inflammation in COPD.…”

“…It is known that ET-1 and NO can both be synthesized by the same cells -epitheliocytes, alveolar macrophages, neutrophils and fibroblasts [9,15]. Activation of these cells during chronic inflammation contributes to the simultaneous release of different vasoactive mediators and thus the joint participation of ET-1 and NO in the progression of the systemic inflammatory process in COPD cannot be excluded.…”