Understanding and Engineering the Pulmonary Vasculature.

Blood vessels play essential roles in regulating embryonic organogenesis and adult tissue homeostasis. The inner lining of blood vessels is covered by vascular endothelial cells, which exhibit tissue-specific phenotypes in term of their molecular signature, morphology, and function. The pulmonary microvascular endothelium is continuous and non-fenestrae to ensure stringent barrier function while allowing efficient gas exchange across the alveoli-capillary interface. During respiratory injury repair, pulmonary microvascular endothelial cells secrete unique angiocrine factors and actively participate in the molecular and cellular events mediating alveolar regeneration. Advances in stem cell and organoid engineering are offering new ways to produce vascularized lung tissue models to investigate vascular-parenchymal interactions during lung organogenesis and pathogenesis. Further, technology developments in 3D biomaterial fabrication are enabling construction of vascularized tissues and microdevices with organotypic features at high resolution to recapitulate the air-blood interface. In parallel, whole-lung decellularization produces biomaterial scaffolds with naturally occurring, acellular vascular bed with preserved tissue architecture and complexity. Emerging efforts in combining cells with synthetic or natural biomaterials open vast opportunities for engineering the organotypic pulmonary vasculature to address current limitations in regenerating and repairing damaged lungs and pave the way towards next-generation therapies for pulmonary vascular diseases.

FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19.

Long non-coding RNAs (lncRNAs) play a significant role in pulmonary hypertension (PH). Our preliminary data showed that hypoxia-induced PH is attenuated by fibroblast growth factor 21 (FGF21) administration. Therefore, we further investigated the regulatory role of long non-coding RNAs in PH treated with FGF21. RNA sequencing analysis and real-time PCR identified a significantly up-regulation of the H19 after FGF21 administration. Moreover, gain- and loss-of-function assays demonstrated that FGF21 suppressed hypoxia-induced proliferation of pulmonary artery smooth muscle cells partially through upregulation of H19. In addition, FGF21 deficiency markedly exacerbated hypoxia-induced increases of pulmonary artery pressure and pulmonary vascular remodelling. In addition, AAV-mediated H19 overexpression reversed the malignant phenotype of FGF21 knockout mice under hypoxia expose. Further investigation uncovered that H19 also acted as an orchestra conductor that inhibited the function of mechanistic target of rapamycin complex 1 (mTORC1) by disrupting the interaction of mTORC1 with eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1). Our work highlights the important role of H19 in PH treated with FGF21 and suggests a mechanism involving mTORC1/EIF4EBP1 inhibition, which may provide a fundamental for clinical application of FGF21 in PH.

Human immunodeficiency viruses and their effect on the pulmonary vascular bed.

December 1, 2021, is "World AIDS Day," reminding us that HIV infection is still widespread and that many of its long-term effects can be deadly. One of these complications is its effect on the pulmonary vascular beds, leading to an increase in the pulmonary pressure, causing the clinical manifestation of "pulmonary hypertension." Unfortunately, we are still far from fully understanding the prevalence, mechanics, and pathobiology of "HIV pulmonary hypertension," especially in Africa and other developing countries where HIV is still common. In addition, the impact of other factors like coinfection and illicit drugs can add and modify the effect on the pulmonary vascular bed, complicating the pathological and clinical effects of HIV. Thus, "World AIDS Day" can be an impetus to pursue further research in this area.

Novel insights on the pulmonary vascular consequences of COVID-19.

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.

Prevalence and severity of hepatopulmonary syndrome and its influence on survival in cirrhotic patients evaluated for liver transplantation.

The prevalence of hepatopulmonary syndrome (HPS) and its influence on survival before and after liver transplantation (LT) remain controversial. Additionally, the chronology of post-LT reversibility is unclear. This study prospectively analyzed 316 patients with cirrhosis who were evaluated for LT in 2002-2007; 177 underwent LT at a single reference hospital. HPS was defined by a partial pressure of arterial oxygen (PaO2 ) <70 mmHg and/or an alveolar-arterial oxygen gradient (A-a PO2 ) ≥20 mmHg in the supine position and positive contrast echocardiography. The prevalence of HPS was 25.6% (81/316 patients), and most patients (92.6%) had mild or moderate HPS. High Child-Pugh scores and the presence of ascites were independently associated with HPS. Patients with and without HPS did not significantly differ in LT waiting list survival (mean 34.6 months vs. 41.6 months, respectively; log-rank, p = 0.13) or post-LT survival (mean 45 months vs. 47.6 months, respectively; log-rank, p = 0.62). HPS was reversed in all cases within 1 year after LT. One-fourth of the patients with cirrhosis who were evaluated for LT had HPS (mostly mild to moderate); the presence of HPS did not affect LT waiting list survival. HPS was always reversed after LT, and patient prognosis did not worsen.

Pediatric Lung Transplantation for Pulmonary Vascular Diseases: Recent Advances and Challenges.

Pediatric lung transplantation for pulmonary vascular diseases has seen notable advancements and trends. Medical therapies, surgical options, and bridging techniques like extracorporeal membrane oxygenation and different forms of transplants have expanded treatment possibilities. Current challenges include ensuring patient adherence to post-transplant therapies, addressing complications like primary graft dysfunction and rejection, and conducting further research in less common conditions like pulmonary veno-occlusive disease and pulmonary vein stenosis. In this review article, the authors will explore the advancements, emerging trends, and persistent challenges in pediatric lung transplantation for pulmonary vascular diseases.

[Highlights of the 55th SEPAR Congress]. / Highlights del 55.° Congreso SEPAR.

The 55th SEPAR Congress was held in Pamplona from 2 to 4 of June 2022. Once again, it was the referral scientific meeting for specialists in pulmonology, thoracic surgery, nursing, physiotherapy, paediatric respiratory diseases and other disciplines involved in respiratory care. The Spanish Society of Pulmonology and Thoracic Surgery showed its national and international leadership in the management of respiratory diseases, which was reflected in a program with an excellent content and a high scientific level. In this review, we offer a summary of some notable aspects covered in six selected areas of interest: pulmonary vascular diseases, non-invasive mechanical ventilation and sleep disorders, asthma, chronic obstructive pulmonary disease (COPD), interstitial lung diseases (ILD), and interventional pulmonolgy and lung transplant.

[Highlights 56th SEPAR Congress]. / Highlights del 56° Congreso SEPAR.

The Spanish Society of Pneumology and Thoracic Surgery (SEPAR) has held its 56th congress in Granada from 8 to 10 June 2023. The SEPAR congress has established itself as the leading scientific meeting for specialists in medicine and respiratory care, reaching a record of participation this year with 2600 attendees. Our society thus demonstrates its leadership in the management of respiratory diseases, as well as its growth and progress in order to achieve excellence. In this review, we offer a summary of some notable issues addressed in six selected areas of interest: chronic obstructive pulmonary disease (COPD), asthma, interstitial lung diseases (ILDs), tuberculosis and respiratory infections, pulmonary circulation, and respiratory nursing.

Adaptation and Maladaptation of the Right Ventricle in Pulmonary Vascular Diseases.

The right ventricle is coupled to the low-pressure pulmonary circulation. In pulmonary vascular diseases, right ventricular (RV) adaptation is key to maintain ventriculoarterial coupling. RV hypertrophy is the first adaptation to diminish RV wall tension, increase contractility, and protect cardiac output. Unfortunately, RV hypertrophy cannot be sustained and progresses toward a maladaptive phenotype, characterized by dilation and ventriculoarterial uncoupling. The mechanisms behind the transition from RV adaptation to RV maladaptation and right heart failure are unraveled. Therefore, in this article, we explain the main traits of each phenotype, and how some early beneficial adaptations become prejudicial in the long-term.

A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: Effects on respiratory functions, functional exercise capacity, physical activity, and quality of life.

BACKGROUND: Impaired respiratory muscle function may be one of the causes of increased dyspnea, reduced exercise capacity, and physical activity (PA), and poor quality of life in pulmonary hypertension (PH). OBJECTIVE: To investigate the effects of threshold inspiratory muscle training (TIMT) on respiratory functions, functional exercise capacity, PA, and QoL in patients with PH. METHODS: Thirty patients with PH were randomly allocated to a TIMT (n = 15) and sham group (n = 15). Three patients in the sham group could not participate in the program. The TIMT group (n = 15) trained at 30% of the maximal inspiratory pressure (MIP), and the sham group (n = 12) performed at lowest pressure without change in threshold pressure. In both groups, patients performed TIMT at home for 15 min, twice per day, with the MIP load determined by the trainer, and were supervised once weekly at the hospital for eight weeks. The primary outcomes were MIP and maximal expiratory pressure (MEP). The secondary outcome measures included spirometric measurements, six-minute walking distance (6MWD), PA (SenseWear armband and International Physical Activity Questionnaire-Short Form-IPAQ-Short Form), and QoL (Minnesota Living with Heart Failure-MLHF). RESULTS: After the training, changes in MIP (p = 0.023) were higher in the intervention group compared with the sham group. Differences in MEP, FEV1 (%), FVC (%), FEV1/FVC (%), 6MWD, %6MWD, IPAQ-SF, MLHFQ, and armband parameters were not significantly different between the groups (p > 0.05). CONCLUSIONS: The results of the study demonstrated that TIMT could increase MIP and did not improve other parameters of respiratory functions, functional exercise capacity, PA, and QoL in patients with PH.

Towards improving the care of children with pulmonary hypertension: The rationale for developing a Pediatric Pulmonary Hypertension Network.

Pulmonary hypertension (PH) and related pulmonary vascular diseases contribute to high morbidity and mortality and treatment options remain limited. Despite the availability of new drug therapies, the long-term outcomes of patients with severe PH remain poor. This may be especially true for many children with PH. Although most clinical studies have emphasized studies of adult patients, PH in pediatrics can be devastating and often contributes to poor outcomes in diverse clinical settings in newborns, infants and children. Unfortunately, studies that address the safety and efficacy of PH therapies in children are rare, as most pharmaceutical studies have focused on the adult population and only in patients with a fairly limited range of associated conditions. Thus, pediatric PH has been understudied and little is understood regarding the natural history, mechanisms of disease, and treatment of childhood PH. Limitations regarding current translational approaches to children with PH are partly due to the relatively small numbers of patients with PH associated with specific pediatric disorders at each center; the small number of well-established, multidisciplinary programs in pediatric PH; little communication between translational and clinician-scientists; and limited interactions between existing PH programs. There is clearly a need to develop clinical infrastructure to better define the natural history and course of pediatric PH, to develop new strategies to identify at-risk patients early in their course, and to establish novel approaches to diagnose, monitor disease progression and treat children with PH. This article discusses the rationale, goals and initial steps in the establishment of an interactive network of investigators, care providers and multidisciplinary teams from several pediatric PH centers.

Registration of vascular structures using a hybrid mixture model.

PURPOSE: Morphological changes to anatomy resulting from invasive surgical procedures or pathology, typically alter the surrounding vasculature. This makes it useful as a descriptor for feature-driven image registration in various clinical applications. However, registration of vasculature remains challenging, as vessels often differ in size and shape, and may even miss branches, due to surgical interventions or pathological changes. Furthermore, existing vessel registration methods are typically designed for a specific application. To address this limitation, we propose a generic vessel registration approach useful for a variety of clinical applications, involving different anatomical regions. METHODS: A probabilistic registration framework based on a hybrid mixture model, with a refinement mechanism to identify missing branches (denoted as HdMM+) during vasculature matching, is introduced. Vascular structures are represented as 6-dimensional hybrid point sets comprising spatial positions and centerline orientations, using Student's t-distributions to model the former and Watson distributions for the latter. RESULTS: The proposed framework is evaluated for intraoperative brain shift compensation, and monitoring changes in pulmonary vasculature resulting from chronic lung disease. Registration accuracy is validated using both synthetic and patient data. Our results demonstrate, HdMM+ is able to reduce more than [Formula: see text] of the initial error for both applications, and outperforms the state-of-the-art point-based registration methods such as coherent point drift and Student's t-distribution mixture model, in terms of mean surface distance, modified Hausdorff distance, Dice and Jaccard scores. CONCLUSION: The proposed registration framework models complex vascular structures using a hybrid representation of vessel centerlines, and accommodates intricate variations in vascular morphology. Furthermore, it is generic and flexible in its design, enabling its use in a variety of clinical applications.

Circulating Endothelial Progenitor Cells Biology and Regenerative Medicine in Pulmonary Vascular Diseases.

Pulmonary vascular disorders (PVDs) include primary or secondary diseases who ultimately influence the right heart function. Several researches showed that stem and progenitor cells may represent a novel approach in treating pulmonary hypertension. In particular, circulating endothelial progenitor cells (EPCs) are mobilized either from the bone marrow and/or arteries to replace dysfunctional endothelial cells and restore blood perfusion to ischemic tissues. They may deliver paracrine signals to stimulate local angiogenesis or may be physically incorporated within neovessels. Understanding the molecular mechanisms utilized by vascular endothelial growth factor (VEGF) to stimulate EPC might shed light on novel targets for regenerative medicine. Ca2+ machinery regulates proliferation, migration, tube formation, and, therefore, differentiation of EPCs may give valuable insights into the biology of these cells; the Ca2+ machinery in these cells is extremely plastic and may vary depending on their origin. In this paper, we review EPCs subtypes, their sources, biological properties, functional mechanisms and of course involvement in pulmonary vascular diseases.

Advances in the Evaluation of Respiratory Pathophysiology during Exercise in Chronic Lung Diseases.

Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple "non-invasive" assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions.

Recent trends in pulmonary arterial hypertension.

Pulmonary hypertension is a serious and unrelenting pulmonary vascular disorder that affects the functional quality of patients and significantly decreases their life span. If diagnosed early, with the number of new therapeutic options that are available, a better quality of life can be provided for a protracted length of time. It is likely that the available treatment will change the natural course of the disease and perhaps prolong survival. As symptoms are often subtle in the early stages of the disease it is imperative that physicians are aware of the manifestations of this condition. A thorough investigation of patients suspected of this condition is essential so that appropriate treatment can be initiated promptly. The routine workup of a patient suspected to have pulmonary hypertension could easily be carried out in any well-equipped peripheral hospital in many affluent and advanced countries. However, it must be mentioned that in some less advanced countries the necessary work up can only be done in major teaching hospitals. Both pulmonologists and cardiologists should be aware of the pathophysiology of pulmonary arterial hypertension, the workup and the treatment options that are available. Patients with refractory pulmonary hypertension should be referred to these research centers for enrolment into any ongoing drug trials as well as for evaluation for heart-lung, single lung, or double lung transplantation. This paper is primarily aimed at pulmonologists and cardiologists taking care of these patients. Unless indicated otherwise this paper mainly deals with WHO group 1 pulmonary hypertension which is designated pulmonary arterial hypertension. Extensive review of the literature spanning the last 30 years was made through Medline using titles such as primary pulmonary hypertension, pulmonary arterial hypertension, secondary pulmonary hypertension, and pulmonary vascular diseases.

Revisión contemporánea: hipertensión pulmonar / Contemporary review: pulmonary hypertension

El término hipertensión pulmonar comprende un grupo heterogéneo de condiciones con la capacidad común de generar incremento progresivo de la presión arterial pulmonar y cuyo resultado final puede derivar en dilatación ventricular derecha, falla cardíaca derecha y muerte. La hipertensión arterial pulmonar es una de sus formas y en las últimas décadas se ha producido un creciente interés sobre esta patología. En parte, mucho es debido al desarrollo y diponibilidad de tratamiento farmacológico e intervensiones específicas para una situación en la que, anteriormente, se contaba con limitados recursos terapéuticos y pronóstico invariablemente sombrío.

The term pulmonary hypertension encompasses a group of heterogeneous conditions with the common capacity to generate progressive increase in pulmonary arterial pressure for wicg the final result may derive in right heart dilatation, failure and death. Pulmonary arterial hypertension is one of its forms and in the last decadens a growing interest for this pathology has been encountered. This is largely due to the development and disposal of pharmacological treatment and specific interventions for a situation for which, in the past, limited resources were available and prognosis was invariably poor.