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For more than 2 years, COVID-19 has been holding the world at awe with new waves of infections, novel mutants, and still limited (albeit improved) means to combat SARS-CoV-2-induced respiratory failure, the most common and fatal presentation of severe COVID-19. In the present perspective, we draw from the successes and—mostly—failures in previous acute respiratory distress syndrome (ARDS) work and the experiences from COVID-19 to define conceptual barriers that have so far hindered therapeutic breakthroughs in this deadly disease, and to open up new avenues of thinking and thus, ultimately of therapy.

Background: Up to 50% of chronic obstructive pulmonary disease (COPD) patients do not receive recommended care for COPD. To address this issue, we developed Proactive Integrated Care (Proactive iCare), a health care delivery model that couples integrated care with remote monitoring. Methods: We conducted a prospective, quasi-randomized clinical trial in 511 patients with advanced COPD or a recent COPD exacerbation, to test whether Proactive iCare impacts patient-centered outcomes and health care utilization. Patients were allocated to Proactive iCare (n=352) or Usual Care ( =159) and were examined for changes in quality of life using the St George’s Respiratory Questionnaire (SGRQ), symptoms, guideline-based care, and health care utilization. Findings: Proactive iCare improved total SGRQ by 7–9 units (p < 0.0001), symptom SGRQ by 9 units (p

Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

Right ventricular failure due to pressure overload and increased wall stress is the cause of morbidity and mortality in patients with severe pulmonary arterial hypertension. While a significant drop in the afterload decreases the stress on the right ventricle (RV), drugs targeting pulmonary hypertension do not achieve a significant and lasting afterload reduction in all patients, and few patients mount a successful long-term adaptation to the increased load resulting in a robustly muscularized and well-perfused RV. Patients that lack this homeostatic resilience of the RV enter into a vicious cycle where inflammatory mediators and cells released by the sick lung circulation and a hyper-activated neuroendocrine system worsen RV function leading to a microvascular angiopathy, capillary rarefaction, and myocardial fibrosis. The presently used vasodilator drugs are unlikely to have significant direct effects on the myocardium with the exception of prostacyclin, which may exert anti-inflammatory and anti-fibrotic actions. Carvedilol, without reducing the PVR, has been shown to improve the RVEF in some patients with severe PAH. A number of catheter-guided and surgical procedures generate shunts and directly unload the RV. A therapy focused directly on the RV is likely to fail when the adaptive responses to the persistent stress of a high afterload, inflammation, and inadequate myocardial perfusion are impaired.

Background The mechanism of vascular remodelling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT). Methods To trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx). Results In the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared with wild-type Su/Hx rats without BM transplantation (P = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats. Conclusions BM-derived cells participate in pulmonary vascular remodelling in the Su/Hx rat model, whereas BM transplantation may contribute to suppression of development of PAH.

Background. Up to 50% of COPD patients do not receive recommended care for COPD. To address this important issue, we developed Proactive Integrated Care (Proactive iCare), a healthcare delivery model that couples integrated care with remote monitoring. Methods. We conducted a prospective, quasi-randomized clinical trial in 511 patients with advanced COPD, or a recent COPD exacerbation, to test whether Proactive iCare impacts patient- centered outcomes and healthcare utilization. Patients were allocated to Proactive iCare (n =352) or Usual Care (n = 159), and were examined for changes in quality of life using the St. Georges Respiratory Questionnaire (SGRQ), symptoms, guideline-based care, and healthcare utilization. Findings. Proactive iCare improved the total SGRQ by 7-9 units (p

It has been generally accepted that severe forms of pulmonary arterial hypertension are associated with inflammation. Plasma levels in patients with severe pulmonary arterial hypertension show elevated levels of interleukins and mediators of inflammation and histologically the diseased small pulmonary arterioles show infiltrates of inflammatory and immune cells. Here, we review the literature that connects pulmonary hypertension with the arachidonic acid/5-lipoxygenase-derived leukotriens. This mostly preclinical background data together with the availability of 5-lipoxygenase inhibitors and leukotriene receptor blockers provide the rationale for testing the hypothesis that 5-lipoxygenase products contribute to the pathobiology of severe pulmonary arterial hypertension in a subgroup of patients.

Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the “quasi-malignancy concept” of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.

Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymic rnu/rnu rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI 2 (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI 2 and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI 2 levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI 2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI 2 and IL-10. Conclusions: In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration-approved medications. Although the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of pulmonary arterial hypertension, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Because only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease.

Background The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog ( MDM2 ) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. Methods This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. Results The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. Conclusions Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.

This Perspective provides an in depth overview of the many aspects of inflammation which are associated with many forms of severe pulmonary hypertension.Details of the pathobiology of severe pulmonary hypertension are discussed in the context of the multicellular inflammatory vascular infiltrates which represent a lung vessel response to injury and and a localized immune response.The important question whether inflammation is cause or consequence of pulmonary hypertension should not distract from designing and conducting clinical pilot studies which examine the efficacy of existing immune system modulating drugs.

Visual Abstract, Highlights • Guided by public sequencing data of iPSC-derived BMPR2-mutant ECs derived from patients with PAH and related family members, SCUBE1 was found to be differentially expressed in ECs carrying BMPR2 mutations, dependent on HIF1A and down-regulated by PAH triggers. • SCUBE1 deficiency controlled BMPR2-associated SMAD1/5/9 signaling, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. • SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with PH due to left heart disease or other acute or chronic pulmonary and cardiovascular diseases. • A plasma SCUBE1 cutpoint of 5.46 ng/ml was defined to distinguish PAH from non-PAH contexts, with a high specificity (0.87) and a significant diagnostic OR (7.6). • In PAH patients, plasma SCUBE1 levels negatively correlated with PA pressure, pulmonary vascular resistance, and RV dysfunction. • These findings support the notion of SCUBE1 as a clinical biomarker of PAH, reflecting the severity and progression of PAH and inherently linked to disease pathogenesis and genetic predisposition., Summary Utilizing publicly available ribonucleic acid sequencing data, we identified SCUBE1 as a BMPR2-related gene differentially expressed between induced pluripotent stem cell-endothelial cells derived from pulmonary arterial hypertension (PAH) patients carrying pathogenic BMPR2 mutations and control patients without mutations. Endothelial SCUBE1 expression was decreased by known triggers of PAH, and its down-regulation recapitulated known BMPR2-associated endothelial pathophenotypes in vitro. Meanwhile, SCUBE1 concentrations were reduced in plasma obtained from PAH rodent models and patients with PAH, whereas plasma concentrations were tightly correlated with hemodynamic markers of disease severity. Taken together, these data implicate SCUBE1 as a novel contributor to PAH pathogenesis with potential therapeutic, diagnostic, and prognostic applications.

Pulmonary arterial hypertension is a fatal disease associated with pulmonary vascular remodeling and right ventricular hypertrophy. Pre-clinical animal models that reproduce the human pulmonary arterial hypertension process and pharmacological response to available therapies are critical for future drug development. The most prevalent animal model reproducing many aspects of angioobliterative forms of pulmonary arterial hypertension is the rat Sugen/hypoxia model in which Sugen, a vascular endothelial growth factor receptor antagonist, primarily causes initiation of endothelial injury and later in the presence of hypoxia promotes proliferation of apoptosis-resistant endothelial cells. We previously demonstrated that exposure of human pulmonary microvascular endothelium to morphine and HIV-proteins results in initial apoptosis followed by increased proliferation. Here, we demonstrate that the double-hit of morphine and Sugen 5416 (Sugen–morphine) in rats leads to the development of pulmonary arterial hypertension with significant medial hypertrophy of pre-acinar pulmonary arteries along with neo-intimal thickening of intra-acinar vessels. In addition, the pulmonary smooth muscle and endothelial cells isolated from Sugen–morphine rats showed hyperproliferation and apoptotic resistance, respectively, in response to serum starvation. Our findings support that the dual hit model of Sugen 5416 and morphine provides another experimental strategy to induce significant pulmonary vascular remodeling and development of severe pulmonary arterial hypertension pathology in rats without exposure to hypoxia.

BackgroundIn animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1–7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1–7) axis in human PAH is incompletely understood.MethodsWe studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1–7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1–9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically.ResultsOf the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72–1.88 pmol·mL−1versus 0.19, 0.10–0.37 pmol·mL−1; p−1versus 12.9, 9.55–19.9 ng·dL−1; p−1versus 4.07, 2.82–6.73 pmol·mL−1; p−1versus 4.53, 1.47–14.3 ng·mL−1; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08–2.81 nmol·mL−1versus 5.97, 3.1–17.8 nmol·mL−1; pConclusionsThe AngII–ACE2–Ang(1–7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.

Background: Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2 +/ - mice. Accordingly, 5-LO and its metabolite, leukotriene B 4 , are candidates for the second hit. The purpose of this study was to determine how 5-LO–mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. Methods: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO–expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2 -mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO–mediated inflammation and were assessed for phenotypic and transcriptomic changes. Results: Lung inflammation, induced by intratracheal delivery of 5-LO–expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2 +/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2 +/- rats gained endogenous 5-LO expression associated with elevated leukotriene B 4 biosynthesis. Bmpr2 -mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO–mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B 4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-β) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation. Conclusions: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2 +/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B 4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.

International audience; In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.

CYPs (cytochrome p450) are critically involved in the metabolism of xenobiotics and toxins. Given that pulmonary hypertension is strongly associated with environmental exposure, we hypothesize that CYPs play a role in the development and maintenance of pathological vascular remodeling.We sought to identify key CYPs that could link drug or hormone metabolism to the development of pulmonary hypertension.We searched in Medline (PubMed) database, as well as http://www.clinicaltrials.gov, for CYPs associated with many key aspects of pulmonary arterial hypertension including, but not limited to, severe pulmonary hypertension, estrogen metabolism, inflammation mechanisms, quasi-malignant cell growth, drug susceptibility, and metabolism of the pulmonary arterial hypertension-specific drugs.We postulate a hypothesis where the AhR (aryl hydrocarbon receptor) mediates aberrant cell growth via expression of different CYPs associated with estrogen metabolism and inflammation.

Heart failure (HF) is usually defined by the dominantly affected heart chamber; therefore, termed right or left HF (RHF or LHF). Pulmonologists understand RHF as a complex syndrome characterized by insufficient delivery of blood from the right ventricle associated with elevated systemic venous pressure at rest or exercise. Cardiologists specify LHF by its clinical functional class and the relation to a reduced (HFrEF), preserved (HFpEF) or mid-range ejection fraction (HFmrEF). Pediatric cardiologist, dealing also with patients with a failing single ventricle, define HF as a condition of insufficient systemic oxygen delivery (DO(2)). Certainly, pediatricians do not think of the right and left heart, or even a single ventricle as an isolated, independently acting entity. Because of the importance of cardiac interactions, the creation of a restrictive atrial communication aims at a palliative approach with the goal to diminish the congestive consequences of a dysfunctional ventricle; further to serve as a pop-off valve in order to prevent syncope and cardiovascular collapse. This review covers the background, the particular indications, the techniques and preliminary results achieved following the creation of a restrictive atrial septum defect (rASD) in different pathophysiological settings. Based on the institutional experience, percutaneous trans-catheter perforation of the atrial septum, followed by gradual balloon dilatation can be performed at any age and location worldwide. Medical institutions in low resource countries can make use of such palliating procedures in the setting of right as well as LHF independent of their pharmacological facilities.

Background/objectives Several studies have already shown the correlation between the right ventricle (RV) hemodynamic values and either glucose uptake or fatty acid uptake in the RV, respectively. However, there are few studies to compare the RV metabolic alteration before and after treatment for pulmonary hypertension. The aims of this study are to assess right ventricular glucose and fatty acid in chronic thromboembolic pulmonary hypertension (CTEPH) patients before and after pulmonary thromboendarterectomy and to examine whether there is a correlation between right ventricular glucose and fatty acid uptake. Methods To assess glucose and fatty acid accumulation in the RV, [ 18 F] fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) and 123 I-β-methyl iodophenyl pentadecanoic acid (BMIPP) imaging were performed in CTEPH patients before (FDG: n=20, BMIPP: n=13) and after (FDG: n=12, BMIPP: n=8) thromboendarterectomy. Results Both [ 18 F] FDG uptake and 123 I-BMIPP uptake in RV of post-PEA patients obviously decreased after this operation procedure (p 18 F] FDG uptake was also significantly correlated with 123 I-BMIPP uptake (r=0.45, p=0.04). Conclusions In this study, we observed that both glucose and fatty acid accumulated in the RV of patients with CTEPH. Although the exact details of the altered energy metabolism in the stressed RV remain unknown, this is the first study to evaluate both glucose and fatty acid uptake before and after thromboendarterectomy in patients with CTEPH, even though the number of the patient is limited.

Major advances in chronic heart failure (cHF) therapy have been achieved and documented in adult patients, while research regarding the mechanisms and therapy of cHF in children has lagged behind. Based on receptor physiological studies and pharmacological knowledge, treatment with specific ß1-adrenergic receptor blocker (ARB), tissue angiotensin-converting enzyme inhibitor (ACE-I), and mineralocorticoid antagonists have to be recommended in children despite lack of sufficient data derived from prospective randomized studies. At our institution, bisoprolol, lisinopril, and spironolactone have been firmly established to treat systolic cHF, hypoplastic left heart syndrome (HLHS) following hybrid approach and congenital left-right shunt diseases, latest in patients where surgery has to be delayed. Chronic therapy with long-acting diuretics and fluid restriction are not advocated because short-term effects are achieved at the expense of further neuro-humoral stimulation. It remains unclear why diuretics are recommended although evidence-based studies, documenting long-term benefit, are missing. However, that is true for all currently used drugs for pediatric cHF. Conclusion: This review focuses on the prevailing “nihilism” of cHF therapy in children with the goal to encourage physicians to treat pediatric cHF with a rationally designed therapy, which combines available agents that have been shown to improve survival in adult patients with cHF. Because of the lack of clinical trials, which generate the needed evidence, surrogate variables like heart and respiratory rate, weight gain, image-derived data, and biomarkers should be monitored and used instead. The recommended pharmacological therapy for systolic heart failure is also provided as the basis for utilizing reversible pulmonary arterial banding (PAB) as a novel strategy in young children with dilative cardiomyopathy (DCM) with preserved right ventricular function. What is Known: • Heart failure (HF) in children is a serious public health concern. • HF has numerous etiologies, but unspecific symptoms. • HF interplays among neuro-humoral, and molecular abnormalities. • Pediatric cHF-therapy is currently based on loop-diuretics, fluid restriction and digoxin. What is New: • Cardiac function analysis has to include cardiac synchrony and VVI. • Considering enormous potential of cardiac regeneration, therapy has to extend with selective ß1-ARB, tissue ACE-I and mineralocorticoid blockers, loop-diuretics avoided as ever possible. • Inhibition of the endogenous neuro-humoral stimulation is monitored by surrogate parameters as heart and breath rate and systolic and diastolic blood pressure. • Advocated HF therapy serves for regenerative strategies as reversible Pulmonary Artery Banding in DCM. Electronic supplementary material The online version of this article (doi:10.1007/s00431-016-2700-3) contains supplementary material, which is available to authorized users.

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Background Impaired angiogenesis is assumed to be an important factor in the development of chronic thromboembolic pulmonary hypertension (CTEPH). However, the role of endothelial cells (ECs) in CTEPH remains unclear. The aim of this study was to investigate the angiogenic potential of ECs from pulmonary endarterectomy (PEA) specimens. Methods We isolated ECs from PEA specimens (CTEPH-ECs) and control EC lines from the intact pulmonary arteries of patients with peripheral lung cancers, using a MACS system. These cells were analyzed in vitro including PCR-array analysis, and the PEA specimens were analyzed with immunohistochemistry. Additionally, the serum HGF levels were determined in CTEPH patients. Results A three-dimensional culture assay revealed that CTEPH-ECs were highly angiogenic. An angiogenesis-focused gene PCR array revealed a high expression of hepatocyte growth factor (HGF) in CTEPH-ECs. The high expression of HGF was also confirmed in the supernatant extracted from PEA specimens. The immunohistochemical analysis showed expression of HGF on the surface of the thrombus vessels. The serum HGF levels in CTEPH patients were higher than those in pulmonary thromboembolism survivors. Conclusion Our study suggests that there are ECs with pro-angiogenetic character and high expression of HGF in PEA specimens. It remains unknown how these results are attributable to the etiology. However, further investigation focused on the HGF pathway may provide novel diagnostic and therapeutic tools for patients with CTEPH. Electronic supplementary material The online version of this article (10.1186/s12890-018-0769-3) contains supplementary material, which is available to authorized users.

BACKGROUND: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.METHODS: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.RESULTS: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.CONCLUSIONS: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Atrial septostomy (AS) is recommended for pulmonary arterial hypertension (PAH)-associated right ventricular (RV) failure, recurrent syncope, or pulmonary hypertensive crisis (PHC). We aimed to evaluate the feasibility and efficacy of AS to manage PAH from infancy to adulthood. From June 2009 to December 2016, transcatheter atrial communications were created in 11 PAH patients (4 girls/women; median age = 4.3 years; range = 33 days–26 years; median body weight = 14 kg; range = 3–71 kg; NYHA-/Ross class IV; n = 11). PAH was classified as idiopathic (n = 6) or secondary (n = 5). History of syncope was dominant (n = 6); two with patent foramen ovale (PFO) admitted with recurrent PHC, three patients required resuscitation before AS. Three patients had PAH-associated low cardiac output. The average pulmonary arterial pressures (PAP systolic/diastolic) were 101/50 (±34/23); the corresponding systemic arterial pressures (SAP) were 99/54 (±23/11); and the mean ratio of PAPd / SAPd was 0.97 (±0.4). Percutaneous trans-septal puncture was uneventfully performed in nine patients; a PFO was dilated in two patients. There was no procedure-related mortality. The median balloon size was 10 mm (range = 6–14 mm); the mean catheter time was 174.6 ± 48 min; fluoroscopy time was 19.8 (±11) min. Syncope and PHC were successfully treated in all patients. The mean arterial oxygen saturation decreased from 97 ± 2 to 89 ± 11.7. One patient died awaiting lung transplantation, one continues to be listed; two patients received a reverse Potts-shunt, one patient died during follow-up; seven patients are stable with PAH-specific treatment. Percutaneous AS is an effective method palliating PAH-associated syncope, PHCs or right (bi-) ventricular heart failure.

A recent study demonstrated a significant role for leukotriene B 4 (LTB 4 ) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB 4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB 4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB 4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein–coupled receptor, BLT1. LTB 4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB 4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

Item does not contain fulltext Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

While significant progress has been made to advance our knowledge of microvascular lesion formation, yet the investigation of how stem-like cells may contribute to the pathogenesis of microvascular diseases is still in its infancy. We assessed whether the inhibitor of DNA binding and differentiation 3 (ID3) contributes to the acquisition of a molecular stem cell-like signature in microvascular endothelial cells. The effects of stable ID3 overexpression and SU5416 treatment - a chemical inducer of microvascular lesions, had on the stemness signature were determined by flow cytometry, immunoblot, and immunohistochemistry. Continuous ID3 expression produced a molecular stemness signature consisting of CD133(+) VEGFR3(+) CD34(+) cells. Cells exposed to SU5416 showed positive protein expression of ID3, VEGFR3, CD34 and increased expression of pluripotent transcription factors Oct-4 and Sox-2. ID3 overexpressing cells supported the formation of a 3-D microvascular lesion co-cultured with smooth muscle cells. In addition, in vivo microvascular lesions from SuHx rodent model showed an increased expression of ID3, VEGFR3, and Pyk2 similar to SU5416 treated human endothelial cells. Further investigations into how normal and stem-like cells utilize ID3 may open up new avenues for a better understanding of the molecular mechanisms which are underlying the pathological development of microvascular diseases.

In PAH, a wide range of abnormal pulmonary vascular manifestations exist, all arising from the endothelium http://ow.ly/IWH2305bXpQ

Anti-interleukin-1 treatment for pulmonary arterial hypertension: are we there yet?http://ow.ly/8irv300EXoo

Improved survival among HIV-1-infected individuals with the advent of antiretroviral therapy has clearly led to a greater prevalence of noninfectious complications. One of the most devastating sequelae in these individuals is the development of pulmonary arterial hypertension (PAH). Various epidemiological studies suggest worse survival of HIV-PAH patients when compared with other forms of PAH. Given that only a subset and not all HIV-infected individuals develop HIV-PAH, it is suggested that an additional second-hit of genetic or environmental trigger is needed for the development of PAH. In this context, it has been well documented that HIV patients who abuse illicit drugs such as stimulants, opioids, and the like, are more susceptible to develop PAH. In this review, we highlight the studies that support the significance of a double hit of HIV and drug abuse in the incidence of PAH and focus on the research that has been undertaken to unravel the pathobiology and vascular remodeling mechanisms underlying the deleterious synergy between HIV infection and drugs of abuse in orchestrating the development of PAH.

Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg−1 nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro , cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover. Prostanoids have load-independent effects on the right ventricle that could contribute to improvement in #PAH

The right ventricle (RV) eventually fails in most patients with severe chronic pulmonary hypertension, however, the individual myocardial reserve and ability to cope with the increased afterload, inflammation and metabolic derangements are highly variable. Hypertrophy is required for the RV to successfully adapt to the chronically elevated pressure and shear stress in the lung vessels. RV hypertrophy associated with an appropriate myocardial capillary density and normal function of the capillary endothelial cells are hallmarks of successful adaptation. Neuroendocrine hyperactivity or overdrive may contribute and facilitate the transition from adaptive RV hypertrophy to RV failure. Therapeutic strategies that reduce cellular stress and modify damaging failure components such as inflammation, lipotoxicity and proteotoxicity need to be explored in order to evaluate whether they can preserve RV function and improve outcome, even when the afterload of the RV cannot be significantly reduced.

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B 4 (LTB 4 ). LTB 4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB 4 was functionally bimodal: Lower LTB 4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB 4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB 4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB 4 stimulated, whereas high concentrations of LTB 4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1 −/− mice were refractory to the beneficial effects of LTB 4 antagonism, suggesting that LTB 4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB 4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB 4 is a promising drug target for the treatment of acquired lymphedema.

Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases characterized by pulmonary vasoconstriction and remodeling of the lung circulation. Although PAH is a disease of the lungs, patients with PAH frequently die of right heart failure. Indeed, survival of patients with PAH depends on the adaptive response of the right ventricle (RV) to the changes in the lung circulation. PAH-specific drugs affect the function of the RV through afterload reduction and perhaps also through direct effects on the myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors, and guanylyl cyclase stimulators may directly enhance myocardial contractility through increased cyclic adenosine and guanosine monophosphate availability. Although this may initially improve cardiac performance, the long-term effects on myocardial oxygen consumption and function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite, as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly considered as a disease with quasimalignant growth of cells in the pulmonary vascular wall, therapies are being developed that inhibit hypertrophy and angiogenesis, and promote apoptosis. The inherent danger of these therapies is a further compromise to the already ischemic, fibrotic, and dysfunctional RV. More recently, the right heart has been identified as a direct treatment target in PAH. The effects of well established therapies for left heart failure, such as β-adrenergic receptor blockers, inhibitors of the renin-angiotensin system, exercise training, and assist devices, are currently being investigated in PAH. Future treatment of patients with PAH will likely consist of a multifaceted approaches aiming to reduce the pressure in the lung circulation and improving right heart adaptation simultaneously.

Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis (RA), and to assess the relation with inflammation.Ninety-six patients (72 females, 24 males; mean age 43.8±11.8 years) with RA and 50 controls (35 females, 15 males; mean age 44.2±11.1 years) were included. From the 12-lead electrocardiogram, Tp-e interval and Tp-e/QT ratio were measured. Blood samples were taken for erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP). These parameters were compared between groups. The relationship between ventricular repolarization and inflammation was assessed by Pearson correlation coefficients.Tp-e interval and Tp-e/QT ratio were increased in RA patients compared to the controls (72.6±8.2 vs 66.4±8.5 ms, 0.20±0.02 vs 0.18±0.02; p0.001 and p0.001, respectively). The Tp-e interval was significantly correlated with CRP, ESR, and disease activity score (DAS-28) (r=0.56, p0.001, r=0.57, p0.001, and r=0.29, p=0.02, respectively). The Tp-e/QT ratio was also correlated with CRP, ESR, and DAS-28 score (r=0.43, p0.001, r=0.53, p0.001, and r=0.25, p=0.03, respectively).In RA patients, the increased frequency of ventricular arrhythmias may be explained by increased indexes of ventricular repolarization and their relationship with inflammation.

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean±sd of 106±7 mmHg in response to SuHx and decreased but remained elevated at 72±8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction.

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

Pulmonary physicians are well aware of drug-induced acute and chronic pulmonary toxicities; inhaled or systemically administered drugs can affect airway tone and cause cough, dyspnoea due to airspace disease, diffuse alveolar damage, pulmonary capillaritis or interstitial lung fibrosis, to name a few presentations and tissue manifestations. Well-studied drugs that cause pulmonary toxicity include methotrexate [1], bleomycin [2] and amiodarone [3], all of which can cause interstitial lung disease, platinum compounds which can generate pulmonary hypersensitivity reactions [4], or propylthiouracil which can cause anti-neutrophil cytoplasmic antibody positive vasculitis and nonspecific interstitial pneumonitis [5, 6]. Over the years a catalogue of drug-induced pulmonary toxicities has been assembled [7] and, more recently, drug-induced respiratory disease in patients with haematological disorders [8] and toxicity related to the systemic treatment of nonsmall cell lung cancer [9] have been reviewed. In contrast, repeated PubMed research of the literature did not uncover a single clinical report of drug-induced emphysema. This circumstance begs the question whether drugs do not cause toxicities that result in alveolar–capillary cell changes and emphysematous lung parenchyma destruction in humans, or whether drug-induced emphysema is simply not reported. Herein, we attempt to approach this topic with the appropriate caution, beginning with the statement that on theoretical ground, and based on data derived from animal studies, there ought to be drugs that cause emphysema in susceptible patients. It has been acknowledged that not all of the patients that develop emphysema are smokers; the estimate is that ∼15% of emphysema patients are nonsmokers [10]. Yet pathogenetic mechanisms that can explain emphysema in these patients are lacking after rare associations, like anorexia [11], cadmium exposure [12] or playing a wind instrument, have been ruled …

Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown.Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells.FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice.VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.

Pathobiological mechanisms that contribute to pulmonary vasoconstriction, lung vascular remodeling, and the development of right heart failure include the generation of reactive oxygen and nitrogen species and the response of lung vascular and cardiac cells to these molecules. We review the information regarding oxidant stress balanced by antioxidant mechanisms and the role of oxidants and antioxidants in hypoxic pulmonary hypertension and their potential role in an animal model of severe pulmonary arterial hypertension (PAH).In human lung tissue from patients with idiopathic PAH, we find reduced superoxide dismutase activity and high expression of the oxidant stress markers nitrotyrosine and 8-OH-guanosine. In the Sugen 5416/chronic hypoxia model of PAH, lung tissue expression of nitrotyrosine and hemeoxygenase 1 (HO-1) is substantial, while HO-1 expression in the failing right ventricle is decreased. This model, based on administration of the VEGF receptor blocker Sugen 5416 and chronic hypoxia (Su/Hx), reproduces many of the characteristic features of severe angioobliterative human PAH. Treatment of Su/Hx rats with protandim, which nuclear factor erythroid-2 related factor (Nrf2)-dependently upregulates the expression of genes encoding antioxidant enzymes, protects against right heart failure without affecting angioobliterative PAH.In human severe PAH, patient survival is determined by the function of the stressed right ventricle; investigation of oxidative and nitrosative stresses and their potential contribution to right heart failure is necessary.Antioxidant therapeutic strategies may be of benefit in the setting of human severe PAH. Whether antioxidant strategies affect lung vascular remodeling and/or prevent right heart failure remains to be examined.

The pulmonary vascular disease component in COPD/emphysema has initially been described by A. Liebow at the dawn of emphysema research [1], and radiologists pointed out that vessel loss on the routine chest X-ray films was the best indicator of emphysema. Benjamin Burrows published the first systematic hemodynamic evaluation of patients with COPD and illustrated the great variability of pulmonary hypertension at rest and during exercise in these patients [2]. Since these early investigations, there have been additional remarkable observations. J. Barbera and coworkers [3] demonstrated histologically the presence of vascular abnormalities in chronic smokers without evidence of pulmonary hypertension (PH); the group of E. Weitzenblum reported severe PH in a subgroup of COPD patients [4] and H.J. Bogaard et al. described a severe reduction in the DLCO in their Dutch cohort of cigarette-smoking patients with idiopathic PH [5]. Finally, it has been recognized that a subset of patients with COPD and with interstitial pulmonary fibrosis has significant PH [6]. It thus appears that chronic cigarette abuse is the common denominator, which can explain an element—or “the element”—of the vascular disease component in a large number of patients with PH, and also that there is a spectrum of severity of PH and of lung vessel pathology.

New Findings • What is the central question of this study? The formation of the cryopyrin inflammasome in the heart induces an intense inflammatory response during acute myocardial infarction, which mediates further damage and promotes adverse cardiac remodelling. The present study investigates the role of interleukin-1β in mediating the pathological effects of the inflammasome in the heart. • What is the main finding and its importance? Blockade of interleukin-1β improves cardiac remodelling after acute myocardial infarction in the mouse by inhibiting apoptosis without affecting the formation or the activity of the inflammasome in the heart. These findings suggest that interleukin-1β mediates the deleterious effects on the heart during the sterile inflammatory response. The formation of the cryopyrin inflammasome in the heart induces an intense inflammatory response during acute myocardial infarction (AMI), which mediates further damage and promotes adverse cardiac remodelling. Active interleukin-1β (IL-1β) is a key product of the inflammasome, being cleaved by active caspase-1. The aim of this study was to dissect the role of IL-1β from that of the inflammasome by using a neutralizing monoclonal antibody directed against IL-1β and measuring the intensity of the inflammatory response, the activity of caspase-1 in the inflammasome, cardiomyocyte apoptosis and cardiac remodelling in a mouse model of non-reperfused AMI. A mouse monoclonal IgG2a antibody directed against IL-1β (IL-1β-AB; 10 mg kg−1) was given i.p. immediately after surgery and repeated 1 week later. Cardiac tissue was analysed at 72 h after surgery in a subgroup of mice for inflammasome aggregates and caspase-1 activity (inflammasome) and for DNA fragmentation and caspase-3 activity (apoptosis). All sham-operated mice were alive at 10 weeks, whereas 40% of the control-antibody-treated mice and 30% of the IL-1β-AB-treated mice died during the 4 weeks after surgery. When compared with vehicle, treatment with the IL-1β-AB did not affect inflammasome formation or caspase-1 activation in the heart tissue at 72 h after AMI nor circulating plasma IL-6 levels, but did inhibit cardiomyocyte apoptosis, limit left ventricular enlargement by 40% (P < 0.01) and improve systolic dysfunction by 17% (P < 0.01) after AMI. These findings suggest that IL-1β mediates the deleterious effects on the heart during the sterile inflammatory response.

From the discovery of hypoxic pulmonary vasoconstriction, responses to hypoxia have been considered as representative for the many alterations in lung vessels that occur in several chronic lung diseases, including pulmonary hypertension, interstitial pulmonary fibrosis, acute respiratory distress syndrome, and chronic obstructive pulmonary disease. An essential part of preclinical research to explain the pathobiology of these diseases has been centered on the exposure of small and large animals to hypoxia. This review aims to summarize pivotal results of clinical and preclinical research on hypoxia, which still have important implications for researchers today.

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6. Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.