Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by proximal pulmonary vascular obstruction by thrombo-fibrotic material, the origin of which has not been elucidated. Enhanced inflammation could contribute to persistent obstruction by impairing pulmonary vascular cell function in CTEPH. We investigated C-reactive protein (CRP) effects on pulmonary vascular cell function in vitro.Primary cultures of proximal pulmonary endothelial cells (ECs) and smooth muscle cells (SMCs) from CTEPH and nonthromboembolic pulmonary hypertension (PH) patients were established. Recombinant CRP effects on mitogenic activity, adhesion capacity, endothelin-1 and von Willebrand factor (vWF) secretion and intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 expression were investigated in ECs and/or SMCs. Expression of the CRP receptor, lectin-like oxidised low-density lipoprotein receptor (LOX)-1, was evaluated in proximal pulmonary arterial tissue and cells by Western blotting and immunofluorescence.CRP increased CTEPH-SMC proliferation by 250%. CRP increased adhesion capacity, endothelin-1 and vWF secretion by CTEPH-ECs by 37%, 129% and 694%, respectively. CRP-induced adhesion of CTEPH-ECs to monocytes was mediated by ICAM-1. CRP had no effect on cells from nonthromboembolic PH patients, probably because of overexpression of LOX-1 in CTEPH. Local expression of CRP was detected in ECs and SMCs within pulmonary arterial tissue.CRP may contribute to persistent obstruction of proximal pulmonary arteries in CTEPH by promoting vascular remodelling, endothelial dysfunction and in situ thrombosis. KEYWORDS: C-reactive protein, chronic thromboembolic pulmonary hypertension, endothelial cells, inflammation, smooth muscle cells C hronic thromboembolic pulmonary hypertension (CTEPH) is one of the main causes of severe pulmonary hypertension. CTEPH is characterised by intraluminal thrombus organisation and fibrous stenosis or complete obliteration of proximal pulmonary arteries. The consequence is an increased pulmonary vascular resistance resulting in pulmonary hypertension (PH) and progressive right heart failure. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodelling. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration [1].To date, the physiopathology of CTEPH remains poorly understood. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation [2]. Besides evidence of dysregulated thrombosis and/or thrombolysis, an elevated prevalence of inflammatory diseases has been observed in CTEPH patients [3]. Accordingly, plasma levels of tumour necrosis factor-a are elevated in CTEPH [4] and elevated pulmonary vascular resistance is correlated with increased expression of the CCL2 chemokine monocyte chemoattractant protein-1 in the plasma and large pulmonary arteries of CTE...

Risk factors detection in chronic thromboembolic pulmonary hypertension, a tool for risk quantification?

“…This can be evoked by immunologic, infl ammatory, or infectious conditions (21,22). Mildly increased C-reactive protein levels in patients without concomitant leukocytosis are more likely correlated with an infl ammatory state caused by chronic heart failure as a consequence of CTEPH than due to an active bacterial infection (23). From these data, we can infer that bacterial DNA within chronic thrombi represents evidence of some previous infection.…”

Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients

“…Another retrospective study reported that the inflammatory marker C-reactive protein was significantly elevated in patients with CTEPH [12]. In a follow-up study, based on their in vitro data, WYNANTS et al [21] postulated that C-reactive protein may contribute to the persistence of obstructing material in pulmonary arteries in CTEPH.…”

Red cell distribution width

“…12 The role of inflammation in CTEPH pathogenesis has been emphasized in studies illustrating the expression of the C-reactive protein receptor lectintype oxidized low-density lipoprotein receptor 1 on cells isolated from the major pulmonary vessels in CTEPH. 35 From the point of chronic inflammatory processes that are involved in the pathogenesis of CTEPH, RDW may potentially reflect the inflammatory status in CTEPH. Release of inflammatory cytokines that may affect bone marrow function and erythrocyte maturation, which is induced by erythropoietin, is inhibited therefore this process may lead increased RDW.…”