scholarly journals Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice

2021 ◽  
Vol 22 (4) ◽  
pp. 1756
Author(s):  
Denise van Uden ◽  
Thomas Koudstaal ◽  
Jennifer A. C. van Hulst ◽  
Ingrid M. Bergen ◽  
Chelsea Gootjes ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Immune Activation ◽  
Regulatory Protein ◽  
Type I ◽  
Tnfaip3 Gene ◽  
Protein Receptor ◽  
Pulmonary Arterial

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.

scholarly journals Pulmonary arterial hypertension in interferonophaties: a case report and a review of the literature

2019 ◽  
Vol 9 (3) ◽  
pp. 204589401986983 ◽  
Author(s):  
A. Trombetta ◽  
S. Ghirardo ◽  
S. Pastore ◽  
A. Tesser ◽  
E. Piscianz ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lupus Erythematosus ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Type I ◽  
Systemic Lupus ◽  
Janus Kinase Inhibitors ◽  
Pulmonary Arterial

Background Pulmonary arterial hypertension consists in an increase of mean pulmonary arterial pressure (PAPm ≥ 25 mmHg), and may lead to right ventricular failure. Pulmonary arterial hypertension can arise in several disorders, encompassing inflammatory conditions and connective tissue diseases. The occurrence of pulmonary arterial hypertension has recently been reported in monogenic interferonopathies and in systemic lupus erythematosus, highlighting the pathogenic role of type I interferons and paving the way to therapies aimed at inhibiting interferon signaling. Case We describe a 17-year-old boy with DNase II deficiency, presenting a clinical picture with significant overlap with systemic lupus erythematosus. During treatment with the Janus kinase inhibitor ruxolitinib, he developed pulmonary arterial hypertension, raising the question whether it could represent a sign of insufficient disease control or a drug-related adverse event. The disease even worsened after drug withdrawal, but rapidly improved after starting the drug again at higher dosage. Summary and conclusion Pulmonary arterial hypertension can complicate type I interferonopathies. We propose that ruxolitinib was beneficial in this case, but the wider role of Janus kinase inhibitors for the treatment of pulmonary arterial hypertension is not clear. For this reason, a strict cardiologic evaluation must be part of the standard care of subjects with interferonopathies, especially when Janus kinase inhibitors are prescribed.

scholarly journals The role of TGF-β or BMPR2 signaling pathway-related miRNA in pulmonary arterial hypertension and systemic sclerosis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Bei Xu ◽  
Guanhua Xu ◽  
Ye Yu ◽  
Jin Lin
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Protein Receptor ◽  
Growth Of Knowledge ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD), causing death in systemic sclerosis (SSc). The past decade has yielded many scientific insights into microRNA (miRNAs) in PAH and SSc. This growth of knowledge has well-illustrated the complexity of microRNA (miRNA)-based regulation of gene expression in PAH. However, few miRNA-related SSc-PAH were elucidated. This review firstly discusses the role of transforming growth factor-beta (TGF-β) signaling and bone morphogenetic protein receptor type II (BMPR2) in PAH and SSc. Secondly, the miRNAs relating to TGF-β and BMPR2 signaling pathways in PAH and SSc or merely PAH were subsequently summarized. Finally, future studies might develop early diagnostic biomarkers and target-oriented therapeutic strategies for SSc-PAH and PAH treatment.

scholarly journals Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension

2014 ◽  
Vol 114 (4) ◽  
pp. 677-688 ◽  
Author(s):  
Peter M. George ◽  
Eduardo Oliver ◽  
Peter Dorfmuller ◽  
Olivier D. Dubois ◽  
Daniel M. Reed ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Receptor Expression ◽  
Type I ◽  
Type I Ifn ◽  
Endothelin 1 ◽  
Gene And Protein Expression ◽  
Pulmonary Arterial

Rationale : Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. Objective : To explore the role of type I IFN in PAH. Methods and Results : Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1 −/− ) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1 −/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions : These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.

scholarly journals The role of genomics and genetics in pulmonary arterial hypertension

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Emilia M Swietlik ◽  
Stefan Gräf ◽  
Nicolas W Morrell
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Gene Encoding ◽  
New Era ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial

[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

2016 ◽  
Vol 15 (1) ◽  
pp. 12-13
Author(s):  
Adaani E. Frost ◽  
Harrison W. Farber
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Transplantation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Donor Organ ◽  
The Road ◽  
Lung Allocation Score ◽  
Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

An Expanding Role of Biomarkers in Pulmonary Arterial Hypertension

2017 ◽  
Vol 18 (6) ◽  
Author(s):  
Mustafa Yildiz ◽  
Alparslan Sahin ◽  
Michael Behnes ◽  
İbrahim Akin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

scholarly journals Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyle A. Batton ◽  
Christopher O. Austin ◽  
Katelyn A. Bruno ◽  
Charles D. Burger ◽  
Brian P. Shapiro ◽  
...  
Keyword(s):  
Sex Differences ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: Role of the peripheral chemoreflex

2021 ◽  
Author(s):  
Marcelle Paula-Ribeiro ◽  
Indyanara C. Ribeiro ◽  
Liliane C. Aranda ◽  
Talita M. Silva ◽  
Camila M. Costa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Early Stage ◽  
Pressure Fluctuations ◽  
Sit To Stand ◽  
Peak Aerobic Capacity ◽  
Pulmonary Arterial ◽  
Peripheral Chemoreflex

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in non-hypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity (i.e., V̇O2peak); and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptors inhibition) or 21% O2 (control session), while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEIALL at rest (mean ± SD: PAH = 0.5 ± 0.2 vs HA = 0.7 ± 0.1 a.u., P = 0.02) and lower cBRSALL (PAH = 6.8 ± 7.0 vs HA = 9.7 ± 5.0 ms mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇O2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in non-hypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇O2peak suggesting it could be functionally relevant.

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