Emerging therapeutics in pulmonary hypertension

Hensley, M.; Levine, Andrea; Lai, Yen‐Chun

doi:10.1152/ajplung.00259.2017

Cited by 28 publications

(23 citation statements)

References 143 publications

(164 reference statements)

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“…In human IPAH lungs and in hypoxia-induced PH in mice, reduced BMPR2 expression-induced macrophage recruitment-involving enhanced production of the chemokine granulocyte macrophage colony-stimulating factor (GM-CSF)-led to the exacerbation of PAH features [126]. In rodent models, such as the MCT-rat, Su/Hx PH mouse model and in mice harboring a human BMPR2 mutation knock-in allele, BMPR2 activation can prevent vascular remodeling and can attenuate the PAH phenotype with endothelial growth and proliferation [127][128][129]. Recently, a therapeutic drug discovery company (MorphogenIX, Cambridge, UK) was founded for the development of BMPs as a novel treatment for PAH.…”

Section: Immunomodulatory Therapy In Pah and Ctephmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

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Section: Immunomodulatory Therapy In Pah and Ctephmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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“…Despite the fact that PH Group-III is the most common and lethal form of PH 9 , clinical studies on these patients have been limited and no conventional PH therapies are approved for use in this patient population 65 . In the present study, we used several tissues derived from PH Group-III patients including HPA, HPV, lung parenchyma and hPASMCs.…”

Section: Resultsmentioning

confidence: 99%

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Özen

Benyahia

Amgoud

et al. 2020

Prostaglandins & Other Lipid Mediators

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Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control;-32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.

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“…The debaters fought passionately with those in the audience, who were the final judges to declare debate winners. As we believe that this discourse is very much needed to advance our understanding of PAH pathogenesis and identify reliable and promising treatment targets (36,42), here, we summarize the main points and counterpoints for each topic to make them available to the broader community with the goal to stimulate further discussion and research. Each argument is prefaced by brief summary of the key points, which are subsequently elaborated in a concise narrative.…”

Section: Introductionmentioning

confidence: 99%

A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017

Kuebler

Nicolls

Olschewski

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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The following review summarizes the pro-con debate about current controversies regarding the pathogenesis of pulmonary arterial hypertension (PAH) that took place at the American Thoracic Society Conference in May 2017. Leaders in the field of PAH research discussed the importance of the immune system, the role of hemodynamic stress and endothelial apoptosis, as well as bone morphogenetic protein receptor-2 signaling in PAH pathogenesis. Whereas this summary does not intend to resolve obvious conflicts in opinion, we hope that the presented arguments entice further discussions and draw a new generation of enthusiastic researchers into this vibrant field of science to bridge existing gaps for a better understanding and therapy of this fatal disease.

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Emerging therapeutics in pulmonary hypertension

Cited by 28 publications

References 143 publications

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017

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