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Comprehensive Physiology Mar 2020The pulmonary blood-gas barrier represents a remarkable feat of engineering. It achieves the exquisite thinness needed for gas exchange by diffusion, the strength to... (Review)
Review
The pulmonary blood-gas barrier represents a remarkable feat of engineering. It achieves the exquisite thinness needed for gas exchange by diffusion, the strength to withstand the stresses and strains of repetitive and changing ventilation, and the ability to actively maintain itself under varied demands. Understanding the design principles of this barrier is essential to understanding a variety of lung diseases, and to successfully regenerating or artificially recapitulating the barrier ex vivo. Many classical studies helped to elucidate the unique structure and morphology of the mammalian blood-gas barrier, and ongoing investigations have helped to refine these descriptions and to understand the biological aspects of blood-gas barrier function and regulation. This article reviews the key features of the blood-gas barrier that enable achievement of the necessary design criteria and describes the mechanical environment to which the barrier is exposed. It then focuses on the biological and mechanical components of the barrier that preserve integrity during homeostasis, but which may be compromised in certain pathophysiological states, leading to disease. Finally, this article summarizes recent key advances in efforts to engineer the blood-gas barrier ex vivo, using the platforms of lung-on-a-chip and tissue-engineered whole lungs. © 2020 American Physiological Society. Compr Physiol 10:415-452, 2020.
Topics: Animals; Bioengineering; Blood-Air Barrier; Humans; Lung; Lung Diseases; Pulmonary Circulation; Pulmonary Gas Exchange
PubMed: 32163210
DOI: 10.1002/cphy.c190026 -
Current Opinion in Pulmonary Medicine Sep 2021While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science... (Review)
Review
PURPOSE OF REVIEW
While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science findings to human disease and even led to recently published studies of metabolic therapy in pulmonary arterial hypertension that are discussed here.
RECENT FINDINGS
Progress has been made in four key areas including mechanisms of insulin resistance in pulmonary arterial hypertension, the role of obesity in pulmonary vascular disease, novel clinical trials targeting metabolism in pulmonary hypertension, and the role of metabolism in chronic thromboembolic pulmonary hypertension.
SUMMARY
: Insulin resistance in pulmonary arterial hypertension is primarily in the lipid axis. There are systemic manifestations of insulin resistance including right ventricular lipotoxicity. Obesity is associated with elevation of right ventricular systolic pressure even in a healthy population and therapies in pulmonary arterial hypertension that target metabolism hold promise for improving exercise, right ventricular function, and visceral adiposity. Finally, there are emerging data that chronic thromboembolic pulmonary hypertension is similarly characterized by metabolic alterations, though the specific metabolites may be different from pulmonary arterial hypertension.
Topics: Heart Ventricles; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Artery; Pulmonary Circulation; Ventricular Function, Right
PubMed: 34127621
DOI: 10.1097/MCP.0000000000000794 -
JACC. Cardiovascular Imaging Jun 2016Imaging plays a central role in the diagnosis and management of all forms of pulmonary hypertension (PH). Although Doppler echocardiography is essential for the... (Review)
Review
Imaging plays a central role in the diagnosis and management of all forms of pulmonary hypertension (PH). Although Doppler echocardiography is essential for the evaluation of PH, its ability to optimally evaluate the right ventricle and pulmonary vasculature is limited by its 2-dimensional planar capabilities. Magnetic resonance and computed tomography are capable of determining the etiology and pathophysiology of PH, and can be very useful in the management of these patients. Exciting new techniques such as right ventricle tissue characterization with T1 mapping, 4-dimensional flow of the right ventricle and pulmonary arteries, and computed tomography lung perfusion imaging are paving the way for a new era of imaging in PH. These imaging modalities complement echocardiography and invasive hemodynamic testing and may be useful as surrogate endpoints for early phase PH clinical trials. Here we discuss the role of magnetic resonance imaging and computed tomography in the diagnosis and management of PH, including current uses and novel research applications, and we discuss the role of value-based imaging in PH.
Topics: Arterial Pressure; Computed Tomography Angiography; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Perfusion Imaging; Predictive Value of Tests; Prognosis; Pulmonary Artery; Pulmonary Circulation; Ventricular Function, Left; Ventricular Function, Right
PubMed: 27282439
DOI: 10.1016/j.jcmg.2015.12.015 -
The Journal of Physiology Sep 2023Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting... (Review)
Review
Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.
Topics: Humans; Pulmonary Circulation; Atrial Fibrillation; Pulmonary Arterial Hypertension; Membrane Potentials; Lung; Potassium Channels, Tandem Pore Domain
PubMed: 37477289
DOI: 10.1113/JP284936 -
Swiss Medical Weekly 2015Elevation of the mean pulmonary arterial pressure to ≥25 mm Hg within the low-pressure system of the pulmonary circulation is defined as pulmonary hypertension.... (Review)
Review
Elevation of the mean pulmonary arterial pressure to ≥25 mm Hg within the low-pressure system of the pulmonary circulation is defined as pulmonary hypertension. Pulmonary hypertension may be the consequence of various clinical and pathophysiological entities. Many of these conditions, however, result in a final common pathway of pathogenesis. This pathway is characterised by the triad of excessive vasoconstriction, microthrombosis and remodelling of pulmonary arteries. Remodelling is arguably the most important factor: its complex pathogenesis is not completely understood and no specific treatment directly targets vascular remodelling. This article aims to review the current understanding of the pathogenesis of pulmonary hypertension and to give insights in future developments in this evolving field.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Circulation; Vascular Remodeling; Vasoconstriction
PubMed: 26479975
DOI: 10.4414/smw.2015.14202 -
Journal of Applied Physiology... Dec 2015The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension, a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This... (Review)
Review
The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension, a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This review describes the time course of this behavior, which occurs in distinct phases, and then explores the importance for HPV of the hypoxia-inducible factor (HIF) pathway. Next, the HIF-hydroxylase enzymes that act as molecular oxygen sensors within the HIF pathway are discussed. These enzymes are particularly sensitive to intracellular iron availability, which confers iron-sensing properties on the HIF pathway. Human studies of iron chelation and supplementation are then reviewed. These demonstrate that the iron sensitivity of the HIF pathway evident from in vitro experiments is relevant to human pulmonary vascular physiology. Next, the importance of iron status in high-altitude illness and chronic cardiopulmonary disease is explored, and the therapeutic potential of intravenous iron discussed. The review concludes by highlighting some further complexities that arise from interactions between the HIF pathway and other intracellular iron-sensing mechanisms.
Topics: Altitude Sickness; Animals; Humans; Hypoxia; Iron; Oxygen Consumption; Pulmonary Circulation; Vasoconstriction
PubMed: 26066825
DOI: 10.1152/japplphysiol.00179.2015 -
Current Hypertension Reports Mar 2015Previously considered a disease isolated to the pulmonary circulation, pulmonary arterial hypertension is now being recognized as a systemic disorder that is associated... (Review)
Review
Previously considered a disease isolated to the pulmonary circulation, pulmonary arterial hypertension is now being recognized as a systemic disorder that is associated with significant metabolic dysfunction. Numerous animal models have demonstrated the development of pulmonary arterial hypertension following the onset of insulin resistance, indicating that insulin resistance may be causal. Recent publications highlighting alterations in aerobic glycolysis, fatty acid oxidation, and the tricarboxylic acid cycle in the pulmonary circulation and right ventricle have expanded our understanding of the complex pathobiology of this disease. By targeting these derangements in metabolism, numerous researchers are investigating noninvasive techniques to monitor disease activity and therapeutics that address the underlying metabolic condition. In the following review, we will explore pre-clinical and clinical studies investigating the metabolic dysfunction seen in pulmonary arterial hypertension.
Topics: Aerobiosis; Animals; Glycolysis; Humans; Hypertension, Pulmonary; Insulin Resistance; Metabolic Syndrome; Oxidation-Reduction; Pulmonary Circulation
PubMed: 25754317
DOI: 10.1007/s11906-014-0524-y -
Arquivos Brasileiros de Cardiologia 2019The finding of pulmonary hypertension (PH) by echocardiography is common and of concern. However, echocardiography is just a suggestive and non-diagnostic assessment of... (Review)
Review
The finding of pulmonary hypertension (PH) by echocardiography is common and of concern. However, echocardiography is just a suggestive and non-diagnostic assessment of PH. When direct involvement of pulmonary circulation is suspected, invasive hemodynamic monitoring is recommended to establish the diagnosis. This assessent provides, in addition to the diagnostic confirmation, the correct identification of the vascular territory predominantly involved (arterial pulmonary or postcapillary). Treatment with specific medication for PH (phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues) has been proven effective in patients with pulmonary arterial hypertension, but its use in patients with PH due to left heart disease can even be damaging. In this review, we discuss the diagnosis criteria, how etiological investigation should be carried out, the clinical classification and, finally, the therapeutic recommendations for PH.
Topics: Echocardiography; Heart Diseases; Humans; Hypertension, Pulmonary; Pulmonary Circulation; Pulmonary Disease, Chronic Obstructive; Risk Assessment
PubMed: 31621783
DOI: 10.5935/abc.20190188 -
Respiration; International Review of... 2017Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder with an estimated prevalence of 1 in 6,000, characterized by recurrent... (Review)
Review
Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder with an estimated prevalence of 1 in 6,000, characterized by recurrent epistaxis, cutaneous telangiectasia, and arteriovenous malformations (AVMs) that affect many organs including the lungs, gastrointestinal tract, liver, and brain. Its diagnosis is based on the Curaçao criteria, and is considered definite if at least 3 of the 4 following criteria are fulfilled: (1) spontaneous and recurrent epistaxis, (2) telangiectasia, (3) a family history, and (4) pulmonary, liver, cerebral, spinal, or gastrointestinal AVMs. The focus of this review is on delineating how HHT affects the lung.
Topics: Arteriovenous Malformations; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Circulation; Telangiectasia, Hereditary Hemorrhagic; Telangiectasis
PubMed: 28850955
DOI: 10.1159/000479632 -
International Journal of Chronic... 2020Pulmonary hypertension (PH) is a frequent and important complication of chronic obstructive pulmonary disease (COPD). It is associated with worse clinical courses with... (Review)
Review
Pulmonary hypertension (PH) is a frequent and important complication of chronic obstructive pulmonary disease (COPD). It is associated with worse clinical courses with more frequent exacerbation episodes, shorter survival, and greater need of health resources. PH is usually of moderate severity and progresses slowly, without altering right ventricular function in the majority of cases. Nevertheless, a reduced subgroup of patients may present disproportionate PH, with pulmonary artery pressure (PAP) largely exceeding the severity of respiratory impairment. These patients may represent a group with an exaggerated vascular impairment (pulmonary vascular phenotype) to factors that induce PH in COPD or be patients in whom idiopathic pulmonary arterial hypertension (PAH) coexist. The present review addresses the current definition and classification of PH in COPD, the distinction among the different phenotypes of pulmonary vascular disease that might present in COPD patients, and the therapeutic approach to PH in COPD based on the available scientific evidence.
Topics: Humans; Hypertension, Pulmonary; Lung; Pulmonary Circulation; Pulmonary Disease, Chronic Obstructive; Ventricular Function, Right
PubMed: 32606641
DOI: 10.2147/COPD.S211841