Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we ...employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects
its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.
The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary ...hypertension (PH). The term “non-PAH PH” summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension that is a progressive, fatal disease. Multiple underlying mechanisms for PAH have been identified, including ...vasoconstriction, intimal proliferation, medial hypertrophy, inflammation, mitochondrial dysfunction, and in situ thrombosis. Because it is an uncommon disease, it has been challenging to identify a specific treatment that targets the dominant disease mechanism in a given patient. Early success demonstrating that some patients (approximately 10%) possess pulmonary vasoreactivity at diagnosis has driven the development of pulmonary vasodilators as the mainstay of treatment. However, while they improve exercise tolerance in clinical trials, their effect on survival is limited. Therapies that target underlying disease mechanisms that affect a majority of patients are clearly needed if we are to significantly improve overall survival.
In the actual guidelines, chronic anticoagulation is no longer recommended in patients with idiopathic, hereditary, and drug-induced PAH although there is much indirect evidence for this.
There are data from over 40 years which include: (1) pathology studies showing the presence of thrombotic lesions in a majority of patients with PAH, both idiopathic and associated with many other conditions; (2) a similar frequency of thrombotic lesions in patients treated with pulmonary vasodilators as was seen in the years before their use; (3) mechanistic studies showing that procoagulant conditions predispose to the development of intraluminal thrombosis that contributes to vascular remodeling and the progressive nature of the pathologic changes; and (4) observational studies that, with one exception, have demonstrated a substantial survival advantage in patients with PAH treated with oral anticoagulation.
Acknowledging that no prospective randomized trial with anticoagulants has ever been done, we recommend a pragmatic approach to the use of anticoagulants in PAH. We suggest that the risks and benefits of chronic anticoagulation be considered in individual patients, and that warfarin be prescribed in patients with PAH, unless they have an increased risk of bleeding.
The question of whether direct oral anticoagulants (DOACs) would provide the same benefit as vitamin K antagonists is valid, but presently there are no data at all regarding their use in PAH. However, in patients with PAH in whom warfarin anticoagulation management proves problematic, it is reasonable to switch the patient to a DOAC as is current practice for other conditions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Diagnosis and Assessment of Pulmonary Arterial Hypertension Badesch, David B., MD; Champion, Hunter C., MD, PhD; Gomez Sanchez, Miguel Angel, MD ...
Journal of the American College of Cardiology,
06/2009, Volume:
54, Issue:
1
Journal Article
Peer reviewed
Open access
The diagnosis and assessment of pulmonary arterial hypertension is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging ...and follow-up assessment. The definition of pulmonary hypertension has been simplified, and is now based on currently available evidence. There has been substantial progress in advancing the imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. The importance of accurate assessment of right ventricular function in following up the clinical course and response to therapy is more fully appreciated. As new therapies are developed for pulmonary arterial hypertension, screening, prompt diagnosis, and accurate assessment of disease severity become increasingly important. A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from our expanding therapeutic armamentarium.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The definition of pulmonary hypertension (PH) is based on a growing body of evidence and represents the result of ongoing discussions within the PH community over the past 50 years. In 2018, the most ...recent World Symposium on Pulmonary Hypertension introduced significant changes in the definition of PH by lowering the mean pulmonary arterial pressure threshold to >20 mmHg and (re)introducing the pulmonary vascular resistance ≥3 WU cut-off for all forms of pre-capillary PH. These changes and their potential clinical impact have been the subject of lively discussions in the community and some important questions and controversies have been identified. In this review we aim to present the development of the definition of PH over the past decades and discuss the main arguments that led to relevant modifications. In addition, we address the practical implications of the most recent changes and controversies that still exist.
To review the historical development of the definition of pulmonary hypertension.To discuss practical implications and current controversies of the currently recommended definitions of pulmonary hypertension and pulmonary arterial hypertension.
Background Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary ...arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension. Methods We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N = 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defined subgroups with a high 2-year mortality. Classification and regression tree analysis was used to determine the incremental prognostic value of combined assessments. Results 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics = 0.77 95% CI 0.70-0.84 and 0.82 95% CI 0.75-0.88, respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics = 0.68 95% CI 0.60-0.76 and 0.74 95% CI 0.66-0.82, respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point. Conclusions 6MWD and BNP values at baseline or week 12 identified a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.
Objectives This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). Background Ambrisentan is an oral, once-daily ...endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. Methods In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. Results After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3× the upper limit of normal was ∼2% per year; most of these events were mild and did not lead to discontinuation of drug. Conclusions Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PCK2), promotes anabolic metabolism in lung cancer cells in the absence of glucose. Here we show considerable heterogeneity of the ...utilization of gluconeogenesis or glycolysis in human non‐small cell lung cancers (NSCLC) and NSCLC metastases and a localization of PCK2 at tumor margins. We identify hypoxia as an important modulator of both pathways in NSCLC cells.
Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non‐small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3‐dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co‐activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with chronic inflammation but the pathological mechanisms are largely unknown. Our study aimed to simultaneously profile a broad ...range of cytokines in the supernatant of pulmonary endarterectomy (PEA) surgical material, as well as prospectively in patients with CTEPH to investigate whether circulating cytokines are associated with haemodynamic and physical characteristics of CTEPH patients. Herein, we show that PEA specimens revealed a significant upregulation of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-γ-induced protein-10 (IP)-10, macrophage inflammatory protein (MIP)1α and RANTES compared to lung tissue from healthy controls. In prospectively collected serum, levels of IL-6, IL-8, IP-10, monokine induced by interferon-γ (MIG) and MIP1α were significantly elevated in CTEPH patients compared to age- and sex-matched healthy controls. In serum of idiopathic pulmonary arterial hypertension (IPAH) patients, only IP-10 and MIG were significantly increased. In CTEPH but not in IPAH, IP-10 was negatively correlated with cardiac index, 6-min walking distance and carbon monoxide diffusion capacity. In vitro, IP-10 significantly increased migration of freshly isolated adventitial fibroblasts. Our study is the first to show that IP-10 secretion is associated with poor pulmonary haemodynamics and physical capacity in CTEPH and might be involved in the pathological mechanism of PEA tissue formation.
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