The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)-κB pro-inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)-8, IL-1β, monocyte chemoattractant protein-1 (MCP-1), C-C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule-1 (VCAM-1) were upregulated in CTEPH-ECs compared to the control cells. To assess the involvement of NF-κB signaling in basal inflammatory activation, CTEPH-ECs were incubated with the NF-κB inhibitor Bay 11-7085. The increase in pro-inflammatory cytokines was abolished when cells were incubated with the NF-κB inhibitor. To determine if NF-κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho-NF-κB-P65 and found that especially the vessels within the thrombus and CTEPH-ECs are positive for phospho-NF-κB-P65. In summary, we show that CTEPH-ECs have a pro-inflammatory status under basal conditions, and blocking NF-κB signaling reduces the production of inflammatory factors in CTEPH-ECs. Therefore, our results show that the increased basal pro-inflammatory status of CTEPH-ECs is, at least partially, regulated through activation of NF-κB signaling and potentially contributes to the pathophysiology and progression of CTEPH.

Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension

“…It has been shown that CTEPH patients presented higher plasma levels of circulating C-reactive protein (CRP) than controls 24 . Additionally, our recent results also identify a basal inflammatory profile of CTEPH-EC 25 . Both studies highlight the important role of NF-kB signaling pathway and CRP in increasing the expression of ICAM-1 and cell adhesion capacity in CTEPH-EC 26,27 .…”

Altered gut microbiota and its association with inflammation in patients with chronic thromboembolic pulmonary hypertension: a single-center observational study in Japan

“…The activation of NFκB signaling may be associated with the pathogenesis of CTEPH. The NFκB signaling is activated in the endothelial cells within organized thrombi in patients with CTEPH [ 46 ], and the expression of inflammatory cytokines is increased [ 46 , 47 ]. The translocation of endotoxin induced by gut dysbiosis, which has recently been called “metabolic endotoxemia” [ 48 ], is associated with chronic low-grade inflammation and the development of cardiovascular diseases [ 13 , 15 ].…”

Potential of C‐X‐C motif chemokine ligand 1/8/10/12 as diagnostic and prognostic biomarkers in idiopathic pulmonary arterial hypertension

“…Besides, a previous study also reports that CXCLs are dysregulated in chronic thromboembolic pulmonary hypertension endothelial cells. 21 Regarding the correlation of CXCL family members with IPAH patients' clinical characteristics, one previous study shows that CXCL10 and CXCL12 are correlated with NT-proBNP, tricuspid annulus plane systolic excursion and right ventricular ejection fraction 10 ; and another study reveals that CXCL13 is associated with CRP in IPAH patients. 11 In the present study, we found that CXCL1 was positively correlated with mPAP and HsCRP, CXCL8 was positively correlated with mPAP and HsCRP, but negatively correlated with 6MWT distance, CXCL10 was positively correlated with mRAP, and CXCL12 was positively correlated with WHO-FC, mPAP, PVR and HsCRP but negatively correlated with 6MWT distance.…”