Search

Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology. Hypoxia inhibits the activity of calcium channels in arterial myocytes by unknown mechanisms and contributes to arterial vasodilation. Here, the authors show that myocyte mitochondria are essential for sensing acute hypoxia and generate signals (NADH and H2O2) that modulate membrane calcium channels. [ABSTRACT FROM AUTHOR]

Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology. Hypoxia inhibits the activity of calcium channels in arterial myocytes by unknown mechanisms and contributes to arterial vasodilation. Here, the authors show that myocyte mitochondria are essential for sensing acute hypoxia and generate signals (NADH and H2O2) that modulate membrane calcium channels. [ABSTRACT FROM AUTHOR]

Purpose: Physical exercise is crucial for healthy aging and plays a decisive role in the prevention of atherosclerotic cardiovascular disease (ASCVD). A higher level of cardiorespiratory fitness (CRF) in the elderly is associated with lower cardiovascular and all-cause mortality. This study investigated the association of CRF level with vascular function and cardiovascular risk factors in the elderly. Methods: We examined 79 apparently healthy and physically active subjects aged > 55 years (64 ± 4 years). Cardiovascular functional parameters assessed included brachial and central blood pressure (BP), pulse wave velocity (PWV), augmentation index (Aix), and ankle-brachial index. Sonography of the common carotid artery was performed. CRF level was determined by a cardiopulmonary exercise test, and everyday activity was quantified with an accelerometer. Results: All participants had a higher CRF level than the reported age-specific normative values. Twenty-nine subjects had subclinical atherosclerosis of the common carotid artery. Compared with participants without atherosclerosis, they were older (p = 0.007), displayed higher brachial systolic BP (p = 0.006), and higher central systolic BP (p = 0.014). Lower brachial (p = 0.036) and central (p = 0.003) systolic BP, lower PWV (p = 0.004), lower Aix (p < 0.001), lower body fat percentage (< 0.001), and lower LDL cholesterol (p = 0.005) were associated with a higher CRF level. Conclusions: In this cohort of healthy and physically active individuals, subjects with subclinical atherosclerosis displayed higher systolic brachial and central BP. A higher CRF level was associated with enhanced vascular function, consistent with an influence of CRF on both BP and vascular function in the elderly. [ABSTRACT FROM AUTHOR]

The document "Cellular ROS and Antioxidants: Physiological and Pathological Role" provides an overview of reactive oxygen species (ROS) and antioxidants and their roles in cellular health and disease. It emphasizes the importance of maintaining a balance between ROS production and antioxidant defense mechanisms. The document explores the dual nature of ROS, discussing both their beneficial and harmful effects, and examines the potential advantages and limitations of antioxidant therapy. It concludes by discussing the significant beneficial effects of antioxidants in reducing the risk of chronic diseases, protecting against aging, and improving immune therapy. The document also highlights the potential deleterious effects of antioxidants and the need for further research to fully understand their biological effects. [Extracted from the article]

Copyright of Innere Medizin (2731-7080) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc-/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc-/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (μCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc-/- mice during aging. However, μCT analyses and stereology showed slightly enhanced signs of agingrelated parameters in p66Shc-/- mice, such as a decline of alveolar density. Accordingly, p66Shc-/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc-/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc-/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc-/- affects the aging process of the lung and the heart differently. While p66Shc-/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging. [ABSTRACT FROM AUTHOR]

Major advances in pulmonary arterial hypertension, pulmonary hypertension (PH) associated with lung disease, and chronic thromboembolic PHcast new light on the pathogeneticmechanisms, epidemiology, diagnostic approach, and therapeutic armamentarium for pulmonary vascular disease. Here, we summarize key basic, translational, and clinical PHreports, emphasizing findings that build on current state-of-the-art research. This review includes cutting-edge progress in translational pulmonary vascular biology, with a guide to the diagnosis of patients in clinical practice, incorporating recent PH definition revisions that continue emphasis on early detection of disease. PHmanagement is reviewed including an overview of the evolving considerations for the approach to treatment of PHin patients with cardiopulmonary comorbidities, as well as a discussion of the groundbreaking sotatercept data for the treatment of pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. [ABSTRACT FROM AUTHOR]

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking, likely contributing to the onset of the human DNA repair condition Fanconi Anaemia. Mutations in the genes coding for FA detoxifying enzymes underlie a human inherited bone marrow failure syndrome (IBMFS), even in the presence of functional DNA repair, raising the question of whether FA causes relevant cellular damage beyond genotoxicity. Here, we report that FA triggers cellular redox imbalance in human cells and in Caenorhabditis elegans. Mechanistically, FA reacts with the redox-active thiol group of glutathione (GSH), altering the GSH:GSSG ratio and causing oxidative stress. FA cytotoxicity is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which metabolizes FA-GSH products, lastly yielding reduced GSH. Furthermore, we show that GSH synthesis protects human cells from FA, indicating an active role of GSH in preventing FA toxicity. These findings might be relevant for patients carrying mutations in FA-detoxification systems and could suggest therapeutic benefits from thiol-rich antioxidants like N-acetyl-L-cysteine. Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products. [ABSTRACT FROM AUTHOR]

Copyright of Der Internist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic Lung Allograft Dysfunction (CLAD) is a life-threatening complication that limits the long-term survival of lung transplantation patients. Early diagnosis remains the basis of efficient management of CLAD, making the need for distinctive biomarkers critical. This explorative study aimed to investigate the predictive power of mitochondrial DNA (mtDNA) derived from bronchoalveolar lavages (BAL) to detect CLAD. The study included 106 lung transplant recipients and analyzed 286 BAL samples for cell count, cell differentiation, and inflammatory and mitochondrial biomarkers, including mtDNA. A receiver operating curve analysis of mtDNA levels was used to assess its ability to detect CLAD. The results revealed a discriminatory pro-inflammatory cytokine profile in the BAL fluid of CLAD patients. The concentration of mtDNA increased in step with each CLAD stage, reaching its highest concentration in stage 4, and correlated significantly with decreasing FEV1. The receiver operating curve analysis of mtDNA in BAL revealed a moderate prediction of CLAD when all stages were grouped together (AUROC 0.75, p-value < 0.0001). This study has found the concentration mtDNA in BAL to be a potential predictor for the early detection of CLAD and the differentiation of different CLAD stages, independent of the underlying pathology. [ABSTRACT FROM AUTHOR]

Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. [ABSTRACT FROM AUTHOR]

Background: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4.These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. Results: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Conclusions: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes. [ABSTRACT FROM AUTHOR]

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking, likely contributing to the onset of the human DNA repair condition Fanconi Anaemia. Mutations in the genes coding for FA detoxifying enzymes underlie a human inherited bone marrow failure syndrome (IBMFS), even in the presence of functional DNA repair, raising the question of whether FA causes relevant cellular damage beyond genotoxicity. Here, we report that FA triggers cellular redox imbalance in human cells and in Caenorhabditis elegans. Mechanistically, FA reacts with the redox-active thiol group of glutathione (GSH), altering the GSH:GSSG ratio and causing oxidative stress. FA cytotoxicity is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which metabolizes FA-GSH products, lastly yielding reduced GSH. Furthermore, we show that GSH synthesis protects human cells from FA, indicating an active role of GSH in preventing FA toxicity. These findings might be relevant for patients carrying mutations in FA-detoxification systems and could suggest therapeutic benefits from thiol-rich antioxidants like N-acetyl-L-cysteine. Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products. [ABSTRACT FROM AUTHOR]

The ability to sense changes in oxygen availability is fundamentally important for the survival of all aerobic organisms. However, cellular oxygen sensing mechanisms and pathologies remain incompletely understood and studies of acute oxygen sensing, in particular, have produced inconsistent results. Current methods cannot simultaneously measure the key cellular events in acute hypoxia (i.e., changes in redox state, electrophysiological properties, and mechanical responses) at controlled partial pressures of oxygen (pO2). The lack of such a comprehensive method essentially contributes to the discrepancies in the field. A sealed microfluidic system that combines i) Raman spectroscopy, ii) patch‐clamp electrophysiology, and iii) live‐cell imaging under precisely controlled pO2 have therefore been developed. Merging these modalities allows label‐free and simultaneous observation of oxygen‐dependent alterations in multiple cellular redox couples, membrane potential, and cellular contraction. This technique is adaptable to any cell type and allows in‐depth insight into acute oxygen sensing processes underlying various physiologic and pathologic conditions. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q<1) and shunting (V/Q=0) is not only caused by impaired hypoxic pulmonary vasoconstriction but also redistribution of perfusion from obstructed lung vessels. Rebalancing the pulmonary vascular tone is a therapeutic challenge. Previous clinical trials on inhaled vasodilators (nitric oxide and prostacyclin) to enhance perfusion to high V/Q areas showed beneficial effects on hypoxaemia but not on mortality. However, specific patient populations with pulmonary hypertension may profit from treatment with inhaled vasodilators. Novel treatment targets to decrease perfusion in low V/Q areas include epoxyeicosatrienoic acids and specific leukotriene receptors. Still, lung protective ventilation and prone positioning are the best available standard of care. This review focuses on disturbed perfusion in ARDS and aims to provide basic scientists and clinicians with an overview of the vascular alterations and mechanisms of V/Q mismatch, current therapeutic strategies, and experimental approaches. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/ Tet-Off system when evaluating those parameters should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS-/- mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown.Experimental Approach: We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice. Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements.Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-l-lysine (L-NIL) was started after emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension.Conclusion and Implications: Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension.Linked Articles: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc. [ABSTRACT FROM AUTHOR]

Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life‐limiting illness with no prospect of cure. PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc [ABSTRACT FROM AUTHOR]

Adaptation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation. Acute oxygen sensing thus is a fundamental pre-requisite for aerobic life. Recent studies unravelled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that regulates the release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase‐derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV). Methods: Vasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs. Results: Pharmacological inhibition of EET synthesis with MS‐PPOH, application of the EET antagonist 14,15‐EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET‐degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre‐contracted with thromboxane mimetic U46619. However, in the presence of KCl‐induced depolarization, 5,6‐EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch‐clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6‐EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential. Conclusions: The EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6‐EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6‐EET‐induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6‐EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV‐related diseases. [ABSTRACT FROM AUTHOR]

Alterations of right atrial (RA) function have emerged as determinants of outcome in pulmonary hypertension (PH). We aimed to clarify the pathophysiological associations of impaired RA conduit function with right ventricular (RV) function in PH. In 51 patients with PH (48 with pulmonary arterial hypertension), RA conduit function was assessed as echocardiographic peak early diastolic strain rate (PEDSR). PEDSR and cardiac magnetic resonance parameters were measured within 24 h of right heart catheterization and generation of pressure-volume loops to assess RV diastolic (RV end-diastolic pressure [EDP] and relaxation [Tau]) and systolic function. Spearman rho correlation and linear regression analysis were used to determine the association of PEDSR with RV function. The impact of PEDSR on time to clinical worsening was assessed using Kaplan-Meier and Cox regression analyses. Median (interquartile range) PEDSR was - 0.56 s - 1 (- 1.08 to - 0.37). Impaired PEDSR was significantly correlated with RV diastolic stiffness [EDP (rho = 0.570; p < 0.001) and Tau (rho = 0.500; p < 0.001)] but not with RV contractility or coupling. In multivariate linear regression including parameters of RV lusitropic and inotropic function, EDP remained independently associated with impaired PEDSR. During a median follow-up of 9 months, 23 patients deteriorated. After multivariate adjustment, PEDSR remained associated with clinical worsening (hazard ratio: 2.85; 95% confidence interval: 1.20-6.78). Altered RV lusitropy is associated with impaired RA conduit phase. PEDSR emerged as a promising, non-invasive, bedside-ready parameter to evaluate RV diastolic function and to predict prognosis in PH. [ABSTRACT FROM AUTHOR]

Breathing faster with HIF2α: In response to hypoxia, glomus cells in the carotid body trigger an increase in ventilation. At the molecular level, hypoxia slows down the electron transport chain in mitochondria, resulting in the accumulation of ROS and NADH, which ultimately activate glomus cells. HIF2α is a hypoxia-induced transcription factor that is highly abundant in glomus cells. Moreno-Domínguez et al. found that HIF2α was necessary for acute responses to hypoxia (see the Focus by Bishop and Ratcliffe). HIF2α mediated the expression of three atypical electron transport chain subunits that were necessary for a rapid buildup of ROS and NADH under hypoxic conditions in glomus cells. Similar to mice deficient in HIF2α in glomus cells, mice that lacked at least one of these atypical electron transport chain subunits in glomus cells also failed to increase ventilation in response to hypoxia. The authors propose that HIF2α target gene expression may set a tissue's acute O2-sensing ability. Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α (Epas1) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia. [ABSTRACT FROM AUTHOR]

Severe inflammatory disorders such as sepsis are a major cause of morbidity and mortality worldwide. Mitochondrial dysfunction is regarded as a key feature involved in inflammation pathogenesis. In the present study, we investigated the impact of the omega‐3 fatty acid‐derived lipid mediator Resolvin E1 (RvE1) on mitochondrial function in experimental pulmonary inflammation. RvE1 was found to exert anti‐inflammatory properties in human alveolar epithelial cells during severe inflammation. RvE1 is capable of restoring inflammation‐induced mitochondrial dysfunction and the impaired imbalance of mitochondrial fission and fusion. Experimental inhibition of mitochondrial fission with Mdivi‐1 in our model is associated with a significantly reduced inflammatory response and improved mitochondrial function. These findings suggest a novel functional mechanism for the beneficial effects of RvE1 in experimental pulmonary inflammatory reactions. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? Hypoxic pulmonary vasoconstriction has never been characterized in isolated mouse pulmonary arteries of different generations in detail. What is the main finding and its importance? We found that only small intrapulmonary arteries (80–200 μm in diameter) exhibit hypoxic pulmonary vasoconstriction. The observed response was sustained, significantly potentiated by depolarization‐induced preconstriction and not dependent on the endothelium or TRPC6 channels. Abstract: Hypoxic pulmonary vasoconstriction (HPV) is a physiological response of pulmonary arteries, which adapts lung perfusion to regional ventilation. The properties of HPV vary significantly between animal species. Despite extensive use of mouse models in studies of HPV, this physiological response has never been characterized in isolated mouse pulmonary arteries in detail. Using wire myography, we investigated the effect of 80 min exposure to hypoxia on the tone in mouse pulmonary arteries of different generations in the presence and absence of preconstriction. Hypoxia induced a sustained relaxation in non‐preconstricted extrapulmonary arteries (500–700 μm in diameter), but not in the presence of KCl‐induced preconstriction. Large intrapulmonary arteries (450–650 μm in diameter) did not exhibit a significant response to the hypoxic challenge. In contrast, in small intrapulmonary arteries (80–200 μm in diameter), hypoxia elicited a slowly developing sustained constriction, which was independent of the endothelium. The response was significantly potentiated in arteries preconstricted with KCl, but not with U46619. Hypoxic pulmonary vasoconstriction was not altered in pulmonary arteries of TRPC6‐deficient mice, which suggests that this response corresponds to the sustained phase of biphasic HPV observed earlier in isolated, buffer‐perfused and ventilated mouse lungs. In conclusion, we have established a protocol that allows the study of sustained HPV in isolated mouse pulmonary arteries. The data obtained might be useful for future studies of the mechanisms of HPV in mice. [ABSTRACT FROM AUTHOR]

Reference 1 Sommer N., Noack S., Hecker A., Hackstein H., Bein G., Weissmann N., Seeger W., Mayer K., Hecker M. Decreased Thymic Output Contributes to Immune Defects in Septic Patients. From Graph to Graph Footnotes 1 B Publisher's Note: b MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Decreased Thymic Output Contributes to Immune Defects in Septic Patients. [Extracted from the article]

Background: Circulating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry. Methods: Patients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan—Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression. Results: 151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan—Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity. Conclusions: Despite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH. [ABSTRACT FROM AUTHOR]

Background: Glycosylated hemoglobin A1c (HbA1c) has been proposed as an independent predictor of long-term prognosis in pulmonary arterial hypertension. However, the clinical relevance of HbA1c in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) remains unknown. The aim of the present study was to investigate the clinical significance of HbA1c as a biomarker in CTEPH. Methods: Prospectively, 102 patients underwent pulmonary endarterectomy (PEA) in our national referral center between March 2013 and March 2014, of which after exclusion 45 patients were analyzed. HbA1c- levels, hemodynamic and exercise parameters were analyzed prior and one-year post-PEA. Results: 45 patients (BMI: 27.3 ± 6.0 kg/m2; age: 62.7 ± 12.3 years) with a mean pulmonary arterial pressure (mPAP) of 43.6 ± 9.4 mmHg, a pulmonary vascular resistance (PVR) of 712.1 ± 520.4 dyn*s/cm5, a cardiac index (CI) of 2.4 ± 0.5 l/min/m2 and a mean HbA1c-level of 39.8 ± 5.6 mmol/mol were included. One-year post-PEA pulmonary hemodynamic and functional status significantly improved in our cohort. Baseline HbA1c-levels were significantly associated with CI, right atrial pressure, peak oxygen uptake and the change of 6-minute walking distance using linear regression analysis. However, using logistic regression analysis baseline HbA1c-levels were not significantly associated with residual post-PEA PH. Conclusions: This is the first prospective study to describe an association of HbA1c-levels with pulmonary hemodynamics and exercise capacity in operable CTEPH patients. Our preliminary results indicate that in these patients impaired glucose metabolism as assessed by HbA1c is of clinical significance. However, HbA1c failed as a predictor of the hemodynamic outcome one-year post-PEA. [ABSTRACT FROM AUTHOR]

In addition to its renowned poisonous effects, carbon monoxide (CO) is being recognized for its beneficial actions on inflammatory and vasoregulatory pathways, particularly when applied at low concentrations via CO-releasing molecules (CO-RMs). In the lung, CO gas and CO-RMs are suggested to decrease pulmonary vascular tone and hypoxic pulmonary vasoconstriction (HPV). However, the direct effect of CO-RMs on the pulmonary vasoreactivity in isolated lungs has not yet been investigated. We assessed the effect of CORM-2 and CORM-3 on the pulmonary vasculature during normoxia and acute hypoxia (1% oxygen for 10 min) in isolated ventilated and perfused mouse lungs. The effects were compared with those of inhaled CO gas (10%). The interaction of CORM-2 or CO with cytochrome P-450 (CYP) was measured simultaneously by tissue spectrophotometry. Inhaled CO decreased HPV and vasoconstriction induced by the thromboxane mimetic U-46619 but did not alter KCl-induced vasoconstriction. In contrast, concentrations of CORM-2 and CORM-3 used to elicit beneficial effects on the systemic circulation did not affect pulmonary vascular tone. High concentration of CO-RMs or long-term application induced a continuous increase in normoxic pressure. Inhaled CO showed spectral alterations correlating with the inhibition of CYP. In contrast, during application of CORM-2 spectrophotometric signs of interaction with CYP could not be detected. Application of CO-RMs in therapeutic doses in isolated lungs neither decreases pulmonary vascular tone and HPV nor does it induce spectral alterations that are characteristic of CO-inhibited CYP. High doses, however, may cause pulmonary vasoconstriction. [ABSTRACT FROM AUTHOR]

Background: Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term effect of different combination regimens of inhaled iloprost and oral sildenafil on survival and disease progression.Methods: This was a retrospective study of patients in the Giessen Pulmonary Hypertension Registry who received iloprost monotherapy followed by addition of sildenafil (iloprost/sildenafil), sildenafil monotherapy followed by addition of iloprost (sildenafil/iloprost), or upfront combination therapy (iloprost + sildenafil). The primary outcome was transplant-free survival (Kaplan-Meier analysis). When available, haemodynamic parameters and 6-minute-walk distance were evaluated.Results: Overall, 148 patients were included. Baseline characteristics were similar across treatment groups; however, the iloprost + sildenafil cohort had higher mean pulmonary vascular resistance and pulmonary arterial pressure than the others. Transplant-free survival differed significantly between groups (P = 0.007, log-rank test). Cumulative transplant-free survival was highest for patients who received iloprost/sildenafil (1 year survival: iloprost/sildenafil, 95.1%; sildenafil/iloprost, 91.8%; iloprost + sildenafil, 62.9%); this group also remained on monotherapy significantly longer than the sildenafil/iloprost group (median 17.0 months vs 7.0 months, respectively; P = 0.004). Compared with pre-treatment values, mean 6-minute-walk distance increased significantly for all groups 3 months after beginning combination therapy.Conclusions: In this observational study of patients with pulmonary hypertension receiving combination therapy with iloprost and sildenafil, cumulative transplant-free survival was highest in those who received iloprost monotherapy initially. However, owing to the size and retrospective design of this study, further research is needed before making firm treatment recommendations. [ABSTRACT FROM AUTHOR]

In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation. [ABSTRACT FROM AUTHOR]

The article discusses a study by R. Ding and colleagues published within the issue, which investigated the mechanism of transcription factor Nur77-mediated inhibition of inflammation in acute lung injury (ALI) using in vitro endothelial cell models and an in vivo knockout mouse model. Topics include the underlying pathogenic mechanisms of ALI in acute respiratory distress syndrome (ARDS), the effect of Nur77 on inflammasome activation, and the relevance of Nur77 in caspase-1 expression.

Purpose of the study: Acute respiratory distress syndrome (ARDS) represents a major cause of mortality in intensive care patients. Activation of peroxisome proliferator-activated receptor-α (PPAR-α) by fibrates, such as WY-14643 (WY), has been described to beneficially influence inflammation and experimental lung injury. The impact of PPAR-α activation on alveolar epithelial cells (AEC) has not been studied yet. Materials and Methods: To investigate the effect of PPAR-α activator WY in wild-type (WT) and in PPAR-α knockout (PPAR-α−/−) animals, mice were treated in different regimes: mice received chow enriched with or without WY for 14 days prior AEC isolation (in-vivo treatment). Furthermore, isolated AEC from both groups were subsequently cultured with or without WY (in-vitro treatment). AEC were stimulated with lipopolysaccharide (LPS). Cell culture supernatant and cell lysate were used for analysis of pro-inflammatory mediators. Results: AEC challenged with LPS showed a significantly increased generation of pro-inflammatory mediators. After in-vivo WY-exposure, AEC displayed significantly reduced concentration of TNF-α, MIP-2, and TxB2 after LPS stimulation. This beneficial effect was abrogated in PPAR-α−/− animals. Interestingly, sole in-vitro application of WY-14643 failed to reduce levels of pro-inflammatory mediators whereas we found an additive effect of a combined in-vivo and in-vitro PPAR-α activation. PGE2 concentration remained high after LPS challenge and was unaffected by WY treatment. Conclusion: PPAR-α activation by in-vivo exposure to fibrates reduced the inflammatory response in isolated AEC. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of ARDS. [ABSTRACT FROM AUTHOR]

Background: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension. Objective: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA. Methods: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed. Results: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 ± 7.6 to 53.8 ± 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 ± 5.6 to 30.3 ± 9.6 mm Hg, cardiac output (CO) from 4.4 ± 0.8 to 6.5 ± 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 ± 4.9 to 20.7 ± 12.7 mm Hg. Post-PEA mPAP increased from 23.7 ± 6.6 at rest to 43.2 ± 7.1 mm Hg, while CO increased to a higher extent from 5.1 ± 0.9 to 8.4 ± 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028). Conclusions: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]