Search

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.

Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6.

Despite the advent of new-generation drug-eluting stents, in-stent restenosis remains a significant problem in patients with coronary artery disease. In- stent restenosis is defined as the gradual re-narrowing of a stented coronary artery lesion due to arterial damage with subsequent local inflammation of the vessel wall and excessive growth of the vascular smooth muscle cells (vSMCs). Four-and-a-half LIM-domain protein 2 (FHL2) is a scaffold protein involved in regulating vSMC function and inflammation. Previously we have demonstrated that FHL2 prevents vSMC proliferation in a murine carotid artery ligation model. However, the effect of FHL2 on the inflammatory response of the vSMCs is not investigated. Therefore, we studied the inflammatory response in the vessel wall of FHL2-deficient (-KO) mice after carotid artery ligation. We found that circulating cytokines and local macrophage infiltration in the ligated carotid vessels were increased in FHL2-KO mice after carotid artery ligation. Moreover, FHL2-KO vSMCs showed increased secretion of cytokines such as SDF-1α and RANTES, and enhanced activation of the NFκB pathway. Finally, we found that blocking the NFκB signalling pathway abrogated this pro-inflammatory state in FHL2-KO vSMCs. Taken together, our results demonstrate that FHL2 decreases the inflammatory response of vSMCs through inhibition of the NFkB-signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation., (Copyright © 2015 by The American Association of Immunologists, Inc.)