Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly characterized by abnormalities of the central lymphatics and may present with nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. CCLA has historically been difficult to diagnose and treat; however, recent advances in imaging, such as dynamic contrast magnetic resonance lymphangiography, and in genomics, such as deep sequencing and utilization of cell-free DNA, have improved diagnosis and refined both genotype and phenotype. Furthermore, in vitro and in vivo models have confirmed genetic causes of CCLA, defined the underlying pathogenesis, and facilitated personalized medicine to improve outcomes. Basic, translational, and clinical science are essential for a bedside-to-bench and back approach for CCLA.
Luciana Daniela Garlisi Torales, Benjamin A. Sempowski, Georgia L. Krikorian, Kristina M. Woodis, Scott M. Paulissen, Christopher L. Smith, Sarah E. Sheppard
Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%–2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide–binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.
Adrienne M. Hammill, Elisa Boscolo
Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.
Annegret Holm, John B. Mulliken, Joyce Bischoff
The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed.
Milena Petkova, Ingvar Ferby, Taija Mäkinen
Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease is characterized by small arteriovenous malformations (AVMs) in mucocutaneous areas (telangiectases) and larger visceral AVMs in the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway. This Review presents up-to-date insights on this mutated signaling pathway and its crosstalk with proangiogenic pathways, in particular the VEGF pathway, that has allowed the repurposing of new drugs for HHT treatment. However, despite the substantial benefits of these new treatments in terms of alleviating symptom severity, this not-so-uncommon bleeding disorder still currently lacks any FDA- or European Medicines Agency–approved (EMA-approved) therapies.
Tala Al Tabosh, Mohammad Al Tarrass, Laura Tourvieilhe, Alexandre Guilhem, Sophie Dupuis-Girod, Sabine Bailly
Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of other nonepithelial cellular components, such as immune, mesenchymal, and endothelial cells, and employment of novel precision gene editing tools have further broadened the range of applications for these systems by providing a microenvironment and/or phenotype closer to the desired in vivo scenario. Thus, these developments in organoid technology have enhanced our ability to model various aspects of lung biology, including pathogenesis of diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, and infectious disease and host-microbe interactions, in ways that are often difficult to undertake using only in vivo models. In this Review, we summarize the latest developments in lung organoid technology and their applicability for disease modeling and outline their strengths, drawbacks, and potential avenues for future development.
Ana I. Vazquez-Armendariz, Purushothama Rao Tata
Advancing age is the most important risk factor for the development of and mortality from acute and chronic lung diseases, including pneumonia, chronic obstructive pulmonary disease, and pulmonary fibrosis. This risk was manifest during the COVID-19 pandemic, when elderly people were disproportionately affected and died from SARS-CoV-2 pneumonia. However, the recent pandemic also provided lessons on lung resilience. An overwhelming majority of patients with SARS-CoV-2 pneumonia, even those with severe disease, recovered with near-complete restoration of lung architecture and function. These observations are inconsistent with historic views of the lung as a terminally differentiated organ incapable of regeneration. Here, we review emerging hypotheses that explain how the lung repairs itself after injury and why these mechanisms of lung repair fail in some individuals, particularly the elderly.
SeungHye Han, G.R. Scott Budinger, Cara J. Gottardi
Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.
Christina Malainou, Shifaa M. Abdin, Nico Lachmann, Ulrich Matt, Susanne Herold
In recent years, there has been an explosion of interest in how fibroblasts initiate, sustain, and resolve inflammation across disease states. Fibroblasts contain heterogeneous subsets with diverse functionality. The phenotypes of these populations vary depending on their spatial distribution within the tissue and the immunopathologic cues contributing to disease progression. In addition to their roles in structurally supporting organs and remodeling tissue, fibroblasts mediate critical interactions with diverse immune cells. These interactions have important implications for defining mechanisms of disease and identifying potential therapeutic targets. Fibroblasts in the respiratory tract, in particular, determine the severity and outcome of numerous acute and chronic lung diseases, including asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and idiopathic pulmonary fibrosis. Here, we review recent studies defining the spatiotemporal identity of the lung-derived fibroblasts and the mechanisms by which these subsets regulate immune responses to insult exposures and highlight past, current, and future therapeutic targets with relevance to fibroblast biology in the context of acute and chronic human respiratory diseases. This perspective highlights the importance of tissue context in defining fibroblast-immune crosstalk and paves the way for identifying therapeutic approaches to benefit patients with acute and chronic pulmonary disorders.
Mohamed A. Ghonim, David F. Boyd, Tim Flerlage, Paul G. Thomas
The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), and chronic obstructive pulmonary disease (COPD). The primary emphasis in the management of these parenchymal disorders has largely revolved around the injury and aberrant repair of epithelial cells. However, there is increasing evidence that the vascular endothelium plays an active role in the development of acute and chronic lung diseases. The endothelial cell network in the capillary bed and the arterial and venous vessels provides a metabolically highly active barrier that controls the migration of immune cells, regulates vascular tone and permeability, and participates in the remodeling processes. Phenotypically and functionally altered endothelial cells, and remodeled vessels, can be found in acute and chronic lung diseases, although to different degrees, likely because of disease-specific mechanisms. Since vascular remodeling is associated with pulmonary hypertension, which worsens patient outcomes and survival, it is crucial to understand the underlying vascular alterations. In this Review, we describe the current knowledge regarding the role of the pulmonary vasculature in the development and progression of ARDS, PF, and COPD; we also outline future research directions with the hope of facilitating the development of mechanism-based therapies.
Izabela Borek, Anna Birnhuber, Norbert F. Voelkel, Leigh M. Marsh, Grazyna Kwapiszewska
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