Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension

Abstract

Objectives:To study the expression of adhesion molecules in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH) and the effects of therapy with the endothelin-1 (ET-1) receptor antagonist, bosentan.Methods:In all, 35 patients with SSc and 25 healthy donors (HD) were selected for this study. Of 35 patients, 10 had isolated PAH assessed by Doppler echocardiography and treated with bosentan. Peripheral blood (PB) lymphocytes were isolated by density gradient centrifugation, and the expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and L-selectin on CD3 T cells was assessed by double immunofluorescence and flow-cytometry. As endothelial activation markers, serum soluble P-selectin, platelet/endothelial cell adhesion molecule (PECAM)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and von Willebrand factor (vWF) antigen were assessed by ELISA. In patients with SSc-PAH, T cell subsets and soluble endothelial markers were assessed at baseline and after 6 and 12 months of bosentan therapy.Results:In patients with SSc-PAH, serum soluble ICAM-1, VCAM-1, P-selectin and PECAM-1 levels were higher than in HD at baseline and fell to normal values after 12 months of bosentan therapy. CD3–LFA1 T cells were significantly higher in PAH-SSc at baseline than in HD or SSc and significantly decreased after therapy. CD3–L-selectin T cells were significantly lower in SSc-PAH at baseline than in HD or SSc and rose to normal levels after bosentan therapy.Conclusions:This study confirms that endothelial activation occurs in SSc, and suggests that changes in the T cell/endothelium interplay take place in SSc-associated PAH. Bosentan seems to be able to hamper these changes and restore T cell functions in these patients.

Soluble CD90 as a potential marker of pulmonary involvement in systemic sclerosis

“…Endothelin-1 is linked to EC activation in patients with PAH and SSc and is associated with serum levels of soluble adhesion molecules. Therefore, it has been shown that sVCAM-1 and sICAM-1 serum levels were elevated in SSc patients with PAH and decreased after initiation of treatment with endothelin receptor blockers (34). In this study, we could not find an association between serum levels of sVCAM-1 or sE-selectin with the presence of PAH or pulmonary fibrosis in SSc.…”

“…Moreover, in a study of 31 SSc patients, it has been shown that sVCAM-1 and sE-selectin are related to internal organ involvement of SSc (16 patients with internal organ involvement: 2 patients with PAH, 13 patients with pulmonary fibrosis, and 1 patient with cardiac involvement) (33). Iannone et al showed that sICAM-1, sP-selectin, soluble platelet EC adhesion molecule 1, and sVCAM-1 were elevated in 10 patients with SSc and PAH in comparison to healthy controls (34). Our study shows for the first time that sCD90 serum concentrations are also elevated in patients with SSc and are related to pulmonary involvement.…”

Relevance of Angiopoietin‐2 and Soluble P‐Selectin Levels in Patients with Pulmonary Arterial Hypertension Receiving Combination Therapy with Oral Treprostinil: A FREEDOM‐C2 Biomarker Substudy

“…23 Furthermore, Ang-2 and sPselectin levels in patients with PAH were found to decrease following treatment with intravenous prostacyclin, and the Ang-2 decrease was associated with an improvement in 6MWD. 7,23 Treatment of PAH with the endothelin receptor antagonist bosentan was also associated with a decrease in sP-selectin levels in one study, 24 whereas another study showed an overall increase. 25 In FREEDOM-C2, background PAH therapy was established and stable in all included patients, with the majority already receiving double combination therapy.…”

“…By contrast, earlier published studies mainly included therapy-naive patients or patients for whom earlier treatment had shown minimal or no efficacy. 7,8,[23][24][25] One can speculate that the background therapy in FREEDOM-C2 had already influenced the biomarker profile at baseline, resulting in low levels that left little opportunity for further reduction by addition of oral treprostinil. Our sP-selectin data provide some support for this: the mean level in our study population at baseline was 76.6 ng/mL, compared with previously reported baseline levels of 243-367 ng/mL in patients with PAH and 99-132 ng/mL in control subjects.…”

“…21 A soluble form of P-selectin (sP-selectin) exists in plasma and is thought to reflect platelet activation and/or endothelial cell injury. 22,23 Increased levels of sP-selectin were found in patients with PAH compared with healthy controls, [23][24][25][26] and administration of intravenous prostacyclin to 18 patients with PAH led to a reduction in sP-selectin levels from baseline after a mean follow-up period of 90 days, suggesting an improvement in endothelial injury and altered hemostasis. 23 Ang-2 and sP-selectin have not yet been extensively investigated in a clinical setting, and data on their response to specific PAH monotherapy or combination therapy are limited; additional data are needed to validate their potential role as biomarkers.…”