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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.
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Subunidade alfa do Fator 1 Induzível por Hipóxia , Mitocôndrias , Oxigênio , Vasodilatação , Animais , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Transdução de Sinais , Masculino , Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Artérias/metabolismo , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/genética , Camundongos Knockout , Transporte de Elétrons , Canais de Cálcio/metabolismo , Canais de Cálcio/genéticaRESUMO
The PEGASUS study is the first multicentric and prospective assessment of the safety of air travel flying in pulmonary hypertension (PH) (NCT03051763). Data of air travel from 60 patients with PH was available. No severe adverse events occurred. Nine patients self-reported mild adverse events during flight (13%), while after landing, 12 patients reported events (20%). Solely one patient (2%) had an adverse event leading to medical consultation. In patients with PH and World Health Organization functional classes II and III, air travel was safe.
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BACKGROUND: Almost all e-cigarettes contain flavorings that make the product more attractive. In the evaluation of e-cigarettes on health, flavors have so far played a subordinate role. METHOD: Selective literature search in PubMed, supplemented by legal regulations on the use of flavors in e-cigarettes. RESULTS: Flavors make it easier to start using e-cigarettes and have a consumption-promoting effect. Deeper inhalation increases nicotine uptake and the absorption of toxic substances from the e-cigarette liquid. For some flavors, pathological effects have been demonstrated in addition to other toxic components of the e-cigarette. To date, no toxicological analyses are available for the vast majority of flavors contained in e-cigarettes. CONCLUSIONS: The proven consumption-promoting effect and the health risks that can be extrapolated from preclinical data are significant for the political discussion of a ban on flavors for e-cigarettes, analogous to the ban on flavors in tobacco products already in force.
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Reactive oxygen species (ROS) are highly reactive oxygen derivatives that include free radicals such as superoxide anion radical (O2â¢-) and hydroxyl radical (HOâ¢), as well as non-radical molecules hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hypochlorous acid (HOCl) [...].
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INTRODUCTION: The study aimed to investigate to what extent acute endurance exercise, especially eccentric exercise and cardiorespiratory fitness affect the metabolic profile of CD4 + cells. METHODS: 15 male, healthy adults aged between 20 and 33 years with a maximal oxygen uptake (VO 2max ) between 44 and 63 ml/kg/min performed a downhill run (DR) and a level run (LR) for 45 minutes at 70% of their VO 2max on a treadmill in a cross-over design. Blood samples were taken before (T0), directly after (T1), 3 hours after (T3), and 24 hours (T24) after each exercise for analyzing leukocyte numbers and cytokine levels. Isolated CD4 + cells were incubated for 4 hours in autologous resting versus 3 hours after exercise serum (T3 DR and T3 LR), and subsequently, cellular respiration, transcriptomic, and metabolomics profiles were measured. RESULTS: The systemic immune inflammation index increased significantly after DR and LR at T1 and T3 (p < .001). In contrast, the transcriptomic and metabolic profile of CD4 + cells showed no significant alterations after incubation in T3 exercise serum. However, cardiorespiratory fitness positively correlated with the maximal mitochondrial respiration in CD4 + cells after incubation with T3 LR serum (r = .617, p = .033) and with gene expression of oxidative phosphorylation and levels of different metabolites. Similarly, VO 2max was associated with an anti-inflammatory profile on RNA level. Lower lactate, methylmalonic acid, and D-gluconic acid levels were found in CD4 + cells of participants with a high VO 2max (p < .001). CONCLUSIONS: Acute exercise leads to a mild pro-inflammatory milieu with only small changes in the metabolic homeostasis of CD4 + cells. High cardiorespiratory fitness is associated with a metabolic shift to oxidative phosphorylation in CD4 + cells. Functional relevance of this metabolic shift needs to be further investigated.
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E-cigarettes are primarily used by teenagers and young adults. Flavors in e-cigarettes increase their attractiveness and encourage young people and adults to start using them. This exposes young people in particular to the risk of nicotine addiction and various toxic substances from the aerosol of e-cigarettes. There are indications that various flavors in e-cigarettes are harmful to health, although toxicological studies are still lacking for the majority of flavors. There is a need for independent scientific investigations in this area. The scientific societies involved are calling for a ban on flavors in e-cigarettes, a ban on disposable e-cigarettes, effective regulation of the sale of e-cigarettes and effective control and implementation of the provisions for the protection of minors.
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Sistemas Eletrônicos de Liberação de Nicotina , Aromatizantes , Sociedades Médicas , Alemanha , Humanos , Pneumologia/legislação & jurisprudênciaRESUMO
BACKGROUND: Almost all e-cigarettes contain flavorings that make the product more attractive. In the evaluation of e-cigarettes on health, flavors have so far played a subordinate role. METHOD: Selective literature search in PubMed, supplemented by legal regulations on the use of flavors in e-cigarettes. RESULTS: Flavors make it easier to start using e-cigarettes and have a consumption-promoting effect. Deeper inhalation increases nicotine uptake and the absorption of toxic substances from the e-cigarette liquid. For some flavors, pathological effects have been demonstrated in addition to other toxic components of the e-cigarette. To date, no toxicological analyses are available for the vast majority of flavors contained in e-cigarettes. CONCLUSIONS: The proven consumption-promoting effect and the health risks that can be extrapolated from preclinical data are significant for the political discussion of a ban on flavors for e-cigarettes, analogous to the ban on flavors in tobacco products already in force.
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Sistemas Eletrônicos de Liberação de Nicotina , Aromatizantes , Humanos , Nicotina/efeitos adversos , Vaping/efeitos adversos , Vaping/legislação & jurisprudênciaRESUMO
Tobacco smoking is widespread in Germany. An increase in the number of teenagers and young adults that smoke has recently been a cause for concern. The high prevalence in Germany is contrasted by inadequate preventive measures compared to international standards. Smoking behavior should always be inquired about and documented in the same way as vital signs. All smokers, regardless of the reason for contact and motivation, should receive short, low-threshold advice, e.g. using the ABC approach (ask, brief advice, cessation). In addition to repeated advice and referral to further services, the use of nicotine replacement or drug therapy is essential for the success of quitting. The combination of long- and short-acting nicotine replacement products doubles the success rate. Electronic nicotine delivery systems are not recommended for smoking cessation.
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Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Dispositivos para o Abandono do Uso de TabacoRESUMO
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 aging-related 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.
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Envelhecimento , Pulmão , Animais , Camundongos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteínas Adaptadoras da Sinalização Shc/genética , Microtomografia por Raio-X , Envelhecimento/genética , Pulmão/diagnóstico por imagem , OxirreduçãoRESUMO
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.
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Aterosclerose , Aptidão Cardiorrespiratória , Humanos , Masculino , Feminino , Aptidão Cardiorrespiratória/fisiologia , Pessoa de Meia-Idade , Aterosclerose/fisiopatologia , Idoso , Pressão Sanguínea/fisiologia , Análise de Onda de Pulso , Índice Tornozelo-Braço , Rigidez Vascular/fisiologiaRESUMO
The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Pneumopatia Veno-Oclusiva , Humanos , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/terapia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/terapia , Pneumopatia Veno-Oclusiva/diagnóstico , Pneumopatia Veno-Oclusiva/genética , Pneumopatia Veno-Oclusiva/terapiaRESUMO
Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) >â20âmmHg, a pulmonary arterial wedge pressure (PAWP) ≤â15âmmHg and a pulmonary vascular resistance of ≤â5 Wood units (WU). Both the non-severe (PVRâ≤â5âWU) and much more the severe PH (PVRâ>â5âWU) have an unfavorable prognosis.If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly.For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended - if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a "pulmonary vascular" phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO <â45â% of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population.
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Hipertensão Pulmonar , Doenças Pulmonares Intersticiais , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Pulmão , Resistência Vascular , Prognóstico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Doenças Pulmonares Intersticiais/complicaçõesRESUMO
BACKGROUND: Atherosclerosis forms the pathological basis for the development of cardiovascular disease. Since pathological processes initially develop without clinically relevant symptoms, the identification of early markers in the subclinical stage plays an important role for initiating early interventions. There is evidence that regulatory T cells (Tregs) are involved in the development of atherosclerosis. Therefore, the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques (SAP). In addition, various lifestyle and risk factors, such as cardiorespiratory fitness, were investigated as associated signatures. METHODS: A cross-sectional study was performed in 79 participants (male: nâ¯=â¯50; ageâ¯=â¯63.6 ± 3.7 years; body mass indexâ¯=â¯24.9 ± 3.1 kg/m²; mean ± SD) who had no previous diagnosis of chronic disease and were not taking medication. Ultrasound of the carotids to identify SAP, cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were performed. Additionally, tests were conducted to assess blood lipids and determine glucose levels. Immunophenotyping of Tregs and their subtypes (resting (rTregs) and effector/memory (mTregs)) was performed by 8-chanel flow cytometry. Participants were categorized according to atherosclerotic plaque status. Linear and logistic regression models were used to analyze associations between parameters. RESULTS: SAP was detected in a total of 29 participants. The participants with plaque were older (64.5 ± 3.6 years vs. 62.9 ± 3.5 years) and had higher peripheral systolic blood pressure (133.8 ± 14.7 mmHg vs. 125.8 ± 10.9 mmHg). The participants with SAP were characterized by a lower percentage of rTregs (28.8% ± 10.7% vs. 34.6% ± 10.7%) and a higher percentage of mTregs (40.3% ± 14.7% vs. 30.0% ± 11.9%). Multiple logistic regression identified age (odds ratio (OR)â¯=â¯1.20 (95% confidence interval (95%CI): 1.01-1.42)) and mTregs (ORâ¯=â¯1.05 (95%CI: 1.02-1.10)) as independent risk factors for SAP. Stepwise linear regression could reveal an association of peak oxygen uptake (ßâ¯=â¯0.441), low-density lipoprotein (LDL) (ßâ¯=â¯-0.096), and SAP (ßâ¯=â¯6.733) with mTregs and LDL (ßâ¯=â¯0.104) with rTregs. CONCLUSION: While at an early stage of SAP, the total proportion of Tregs gives no indication of vascular changes, this is indicated by a shift in the Treg subgroups. Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators. This could be used to initiate lifestyle-based preventive measures at an early stage, which may have a protective effect against disease progression.
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BACKGROUND: COPD is an incurable disease and a leading cause of death worldwide. In mice, fibroblast growth factor (FGF)10 is essential for lung morphogenesis, and in humans, polymorphisms in the human FGF10 gene correlate with an increased susceptibility to develop COPD. METHODS: We analysed FGF10 signalling in human lung sections and isolated cells from healthy donor, smoker and COPD lungs. The development of emphysema and PH was investigated in Fgf10+/- and Fgfr2b+/- (FGF receptor 2b) mice upon chronic exposure to cigarette smoke. In addition, we overexpressed FGF10 in mice following elastase- or cigarette smoke-induced emphysema and pulmonary hypertension (PH). RESULTS: We found impaired FGF10 expression in human lung alveolar walls and in primary interstitial COPD lung fibroblasts. In contrast, FGF10 expression was increased in large pulmonary vessels in COPD lungs. Consequently, we identified impaired FGF10 signalling in alveolar walls as an integral part of the pathomechanism that leads to emphysema and PH development: mice with impaired FGF10 signalling (Fgf10+/- and Fgfr2b+/- ) spontaneously developed lung emphysema, PH and other typical pathomechanistic features that generally arise in response to cigarette smoke exposure. CONCLUSION: In a therapeutic approach, FGF10 overexpression successfully restored lung alveolar and vascular structure in mice with established cigarette smoke- and elastase-induced emphysema and PH. FGF10 treatment triggered an initial increase in the number of alveolar type 2 cells that gradually returned to the basal level when the FGF10-mediated repair process progressed. Therefore, the application of recombinant FGF10 or stimulation of the downstream signalling cascade might represent a novel therapeutic strategy in the future.
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Fumar Cigarros , Enfisema , Hipertensão Pulmonar , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Animais , Camundongos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Hipertensão Pulmonar/complicações , Elastase Pancreática/efeitos adversos , Elastase Pancreática/metabolismo , Fator 10 de Crescimento de Fibroblastos/metabolismo , Fator 10 de Crescimento de Fibroblastos/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/uso terapêutico , Fumar Cigarros/efeitos adversos , Enfisema Pulmonar/etiologia , Pulmão/metabolismo , Enfisema/complicações , Camundongos Endogâmicos C57BLRESUMO
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.
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Ácidos Graxos Ômega-3 , Síndrome do Desconforto Respiratório , Animais , Camundongos , Encéfalo , Cromatografia Líquida , Inflamação , Lipopolissacarídeos/toxicidade , Pulmão , Camundongos Knockout , Receptores do Leucotrieno B4 , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/genética , Espectrometria de Massas em TandemRESUMO
Major advances in pulmonary arterial hypertension, pulmonary hypertension (PH) associated with lung disease, and chronic thromboembolic PH cast new light on the pathogenetic mechanisms, epidemiology, diagnostic approach, and therapeutic armamentarium for pulmonary vascular disease. Here, we summarize key basic, translational, and clinical PH reports, 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. PH management is reviewed including an overview of the evolving considerations for the approach to treatment of PH in patients with cardiopulmonary comorbidities, as well as a discussion of the groundbreaking sotatercept data for the treatment of pulmonary arterial hypertension.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Embolia Pulmonar , Doenças Vasculares , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Hipertensão Arterial Pulmonar/complicações , Pulmão , Hipertensão Pulmonar Primária Familiar/complicações , Doença Crônica , Embolia Pulmonar/complicaçõesRESUMO
Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.
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Enfisema , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Antígenos CD/metabolismo , Antioxidantes , Moléculas de Adesão Celular/metabolismo , Proteínas Ligadas por GPI/efeitos adversos , Proteínas Ligadas por GPI/metabolismo , Heme Oxigenase-1/metabolismo , Estresse Oxidativo , NicotianaRESUMO
Background: Volume overload is often associated with clinical deterioration in precapillary pulmonary hypertension (PH). However, thorough assessment of volume overload is complex and therefore not routinely performed. We examined whether estimated plasma volume status (ePVS) is associated with central venous congestion and prognosis in patients with idiopathic pulmonary arterial hypertension (IPAH) or chronic thromboembolic PH (CTEPH). Methods: We included all patients with incident IPAH or CTEPH enrolled in the Giessen PH Registry between January 2010 and January 2021. Plasma volume status was estimated using the Strauss formula. Results: In total, 381 patients were analyzed. Patients with high ePVS (≥4.7 vs. <4.7â ml/g) at baseline showed significantly increased central venous pressure (CVP; median [Q1, Q3]: 8 [5, 11] mmHg vs. 6 [3, 10] mmHg) and pulmonary arterial wedge pressure (10 [8, 15] mmHg vs. 8 [6, 12] mmHg), while right ventricular function was not altered. In multivariate stepwise backward Cox regression, ePVS was independently associated with transplant-free survival at baseline and during follow-up (hazard ratio [95% confidence interval]: 1.24 [0.96, 1.60] and 2.33 [1.49, 3.63], respectively). An intra-individual decrease in ePVS was associated with a decrease in CVP and predicted prognosis in univariate Cox regression. Patients with high ePVS without edema had lower transplant-free survival than those with normal ePVS without edema. In addition, high ePVS was associated with cardiorenal syndrome. Conclusions: In precapillary PH, ePVS is associated with congestion and prognosis. High ePVS without edema may represent an under-recognized subgroup with poor prognosis.
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BACKGROUND: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. RESULTS: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8â months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8â cells·mL-1; control: 37.0±21.1â cells·mL-1; NF ECV: 198.6±94.9â cells·mL-1) and in lung tissue (ECV: 25.7±3.3â cells·mm-3; control: 4.8±1.1â cells·mm-3; NF ECV: 14.1±2.2â cells·mm-3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. CONCLUSIONS: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations.