Extracellular Vesicles: Multimodal Tools for Diagnosis, Prognosis, and Therapy in Respiratory Diseases

Keywords: interstitial lung disease; lung function; paediatric lung disease; pulmonary vascular disease; sleep

Mesenchymal stromal cells (MSCs) as a kind of pluripotent adult stem cell have shown great therapeutic potential in relation to many diseases in anti-inflammation and regeneration. The results of preclinical experiments and clinical trials have demonstrated that MSC-derived secretome possesses immunoregulatory and reparative abilities and that this secretome is capable of modulating innate and adaptive immunity and reprograming the metabolism of recipient cells via paracrine mechanisms. It has been recognized that MSC-derived secretome, including soluble proteins (cytokines, chemokines, growth factors, proteases), extracellular vesicles (EVs) and organelles, plays a key role in tissue repair and regeneration in bronchopulmonary dysplasia, acute respiratory distress syndrome (ARDS), bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension, and silicosis. This review summarizes the known functions of MSC-EV modulation in lung diseases, coupled with the future challenges of MSC-EVs as a new pharmaceutical agent. The identification of underlying mechanisms for MSC-EV might provide a new direction for MSC-centered treatment in lung diseases.Graphical abstract

The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart–Lung Transplant Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant

The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth Official Adult Lung and Heart-Lung Transplantation Report—2009

Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep.

NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension

Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types—including mesenchymal stromal cells (MSCs)—under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.

Pulmonary Hypertension: From an Orphan Disease to a Public Health Problem

Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary fibrosis (IPF) are increasingly recognized as important contributors to mortality and morbidity worldwide. Among others, the current treatment paradigm considers broad inhibition of receptor tyrosine kinases, a strategy that likely leads to collateral inhibition of signaling pathways that are critical for lung repair and regeneration. Fibroblast growth factor 7 (FGF7) and FGF10 signaling in the lung through FGF receptor 2 (FGFR2) are involved in epithelial cell protection and renewal, and mutations in their corresponding genes in humans are linked to increased susceptibility to lung pathologies, such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. In this report, we present data demonstrating significant upregulation of FGF7, FGF10, and FGFR2 in IPF and IPAH lungs compared with donor lungs. These ligands and their cognate receptor converged on the remodeled parenchyma and vasculature of IPF and IPAH lungs. Interestingly, the expression levels of FGFR1, which has been previously shown to play a pathological role in PH development, were not significantly changed in either disease state. Intriguingly, the expression levels of FGF7, FGF10, and FGFR2 were lower in IPF lung regions undergoing active remodeling, and inversely correlated with IPAH severity, indicating that increased expression might reflect lung repair rather than lung pathology, and warranting further research on the precise role of FGF signaling in pulmonary parenchymal and vascular remodeling.

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …

Extracellular vesicles (EVs), as part of the cellular secretome, have emerged as essential cell–cell communication regulators in multiple physiological and pathological processes. Previous studies have widely reported that mesenchymal stromal cell-derived EVs (MSC-EVs) have potential therapeutic applications in ischemic diseases or regenerative medicine by accelerating angiogenesis. MSC-EVs also exert beneficial effects on other vasculopathies, including atherosclerosis, aneurysm, vascular restenosis, vascular calcification, vascular leakage, pulmonary hypertension, and diabetic retinopathy. Consequently, the potential of MSC-EVs in regulating vascular homeostasis is attracting increasing interest. In addition to native or naked MSC-EVs, modified MSC-EVs and appropriate biomaterials for delivering MSC-EVs can be introduced to this area to further promote their therapeutic applications. Herein, we outline the functional roles of MSC-EVs in different vasculopathies and angiogenesis to elucidate how MSC-EVs contribute to maintaining vascular system homeostasis. We also discuss the current strategies to optimize their therapeutic effects, which depend on the superior bioactivity, high yield, efficient delivery, and controlled release of MSC-EVs to the desired regions, as well as the challenges that need to be overcome to allow their broad clinical translation.

Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), emphysema, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension and others contribute significantly to morbidity and mortality worldwide, yet successful...

IntroductionThe immunopathogenesis of end-stage chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remains poorly understood. Emerging evidence suggests that distinct T cell subpopulations may play critical roles in the progression of both diseases. A better understanding of these roles could provide important insights into underlying mechanisms and guide the development of targeted therapies.MethodsWe performed flow cytometric analysis of explanted lung tissue from patients with advanced COPD (n = 9), IPF (n = 9), and idiopathic pulmonary arterial hypertension (IPAH, n = 3) undergoing lung transplantation. Healthy donor lung tissue (n = 7) served as controls.ResultsBoth COPD and IPF lungs demonstrated an increased frequency of Th1 (CXCR3+CCR4-CCR6-) lymphocytes compared to controls. In contrast, Tc17 cells were significantly reduced. No notable differences were observed in Th2, Th17, or Tc1 cell populations. Activated CD4+ T cells (CD69+CD25+HLA-DR-/+) were significantly enriched in IPF compared to COPD and donor lungs. COPD lungs exhibited a marked expansion of terminally differentiated cytotoxic CD8+CD28-CD27- T cells. In double-negative (DN; CD3+CD4-CD8-) T cell compartment, CD25+ T cells were increased in COPD, whereas DN tissue-resident memory (TRM; CD69+CD25-HLA-DR-) cells were reduced in both COPD and IPF. Invariant natural killer T (iNKT; Vα24+Vβ11+) cell levels were uniformly low without intergroup differences.DiscussionOur findings identify disease-specific immune signatures in end-stage COPD and IPF. Th1 cell expansion together with a reduction in Tc17 and DN TRM subsets represented shared features of COPD and IPF, whereas accumulation of terminally differentiated cytotoxic CD8+ T cells and CD25+ DN T cells was specific to COPD. These findings enhance our understanding of adaptive immune dysregulation in COPD and IPF and may support the development of immunomodulatory strategies.

Critical roles of interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) in pulmonary disorders.

Transfer of microRNA-486-5p from human endothelial colony forming cell–derived exosomes reduces ischemic kidney injury