European Respiratory Review最新文献

Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease primarily affecting women, manifested as cystic lung destruction, angiomyolipomas (AMLs) and lymphagioleiomyomas. The hallmark of LAM is the presence of abnormal perivascular epithelioid cells, referred to as LAM cells. LAM is classified into tuberous sclerosis-associated (TSC) and sporadic forms according to the presence or absence of TSC gene mutations. In recent decades, the benefit of mechanistic target of rapamycin (mTOR) inhibitors has been demonstrated in stabilising respiratory function, reducing AMLs, lymphangioleiomyoma and chylous effusions, and controlling TSC-associated seizures. In addition to mTOR inhibition, clinical trials have explored therapies targeting autophagy, receptors of tyrosine kinases (RTKs), nonreceptor tyrosine kinases (non-RTKs) and hormones. More recently, new treatments avenues involving immune microenvironment, histamine signalling and Src kinase inhibition have entered pre-clinical and/or clinical evaluation. This review summarises the multiple pathophysiological mechanisms in LAM and highlights the therapeutic targets identified to date. Several clinical trials have been described, offering insights into their potential application and further research.

Great strides have been made in pre-clinical research in recent decades using animal models and cell lines. However, traditional models may fail to translate to humans, resulting in substantial failure rates in drug development. Recent three-dimensional organoid models have borne a good resemblance to the architecture, development and function of tissues, especially for organs with complex cell interactions and dynamics such as the lungs. In 2022, the role of organoids as alternative to animal testing was recognised by the US Food and Drug Administration. We searched Medline and ClinicalTrials.gov for studies on the experimental use of lung organoids to model disease pathogenesis and test treatments for paediatric and neonatal respiratory diseases. We comprehensively review the translational value of organoids for paediatric and neonatal respiratory conditions, with current limitations and future expectations, while glancing at other in vitro respiratory models. Combinations of organoid models varying in derivation and differentiation have been used to test interventions for conditions such as infectious/inflammatory diseases, abnormalities of the lung vasculature, surfactant deficiency and genetic diseases. Even multifactorial diseases such as congenital diaphragmatic hernia and bronchopulmonary dysplasia are benefiting from new options for patient-specific sampling and organoid derivation. Microscale technologies and engineering contribute to further advancements in lung-on-chip and microfluidic environments. Overall, organoids show great potential as a bridge between basic research and clinical applications, with versatile adaptability to research purposes. Patient-derived organoids carry exciting possibilities for both personalised medicine and clinical research. Rapid advances in regenerative medicine and engineering have opened up new avenues for neonatology and paediatric respiratory medicine.

Several interstitial lung diseases (ILDs) with different aetiologies and pathogenic mechanisms may exhibit a progressive behaviour, similar to idiopathic pulmonary fibrosis, with comparable functional decline and early mortality. Progressive pulmonary fibrosis (PPF) is not a diagnosis but rather reflects a clinical phenotype. Identifying progression is challenging as variability exists, both between different ILDs as well as in the context of the same entity. The American Thoracic Society/European Respiratory Society guidelines provide a useful framework for recognising the progressive behaviour of individual ILDs. Nevertheless, sometimes the "one-size-fits-all" approach to PPF may not lead to the best management decisions for individual patients. Real-life clinical practice presents multiple hurdles for practising clinicians and it is of utmost importance to target early those individuals that will benefit from antifibrotic treatment. This review aims to highlight several clinical points and suggest that, in certain cases, the strict rule of initiating antifibrotic treatment only upon disease progression may warrant some flexibility, particularly in the context of everyday clinical practice. Emphasis is placed on critically examining the criteria used to define progression across different ILDs, commenting on clinical issues such as disease severity at baseline, prevention of acute exacerbations, the definition of "standard treatment", the need for early access to appropriate treatment, prediction of progression, personalised medicine and an aetiologic approach. Engaging technology and artificial intelligence will play a role in the future. Until then, the best possible management decisions will rely on the judgment of treating clinicians, guided by existing evidence and patient needs.

Bronchiectasis is a chronic respiratory disease characterised by irreversible bronchial dilation, persistent productive cough and alternating periods of clinical stability and exacerbations. The distorted airways impair mucus clearance, making them susceptible to recurrent infections and chronic inflammation. Haemophilus influenzae is a common pathogen in bronchiectasis according to international registries. It employs several virulence mechanisms, including adhesion, intracellular invasion/survival, biofilm formation and evasion of antibiotic treatments, to establish infection. These mechanisms allow H. influenzae to persist in the respiratory tract and evade host immune defences. Although its role is well-documented in other airway diseases, the impact of H. influenzae in bronchiectasis remains incompletely understood. International guidelines do not recommend eradication therapy for H. influenzae upon first isolation, while this intervention is advised for Pseudomonas aeruginosa in such cases. Long-term immunomodulatory treatment with macrolides is an option for patients with bronchiectasis with chronic H. influenzae infection and frequent exacerbations, though it carries the risk of promoting antibiotic resistance and a Pseudomonas-enriched airway microbiome. Studies indicate significant negative interactions between P. aeruginosa and H. influenzae, suggesting a competitive relationship that can influence microbiome dynamics and potentially affect clinical outcomes. Currently, there is insufficient evidence to support vaccination against nontypeable H. influenzae in chronic airways disease. Despite its frequent detection in respiratory samples, the precise role of H. influenzae in bronchiectasis-related morbidity and disease progression is not fully understood and warrants further investigation. This review examines the impact of H. influenzae on bronchiectasis pathophysiology and progression, comparing its role in other chronic respiratory diseases.

Respiratory diseases are major causes of chronic disorders and death worldwide, involving inflammatory, tumoral or infectious processes. It has been proven that vascular mechanisms are key contributors to the pathogenesis of these diseases. For that purpose, it is essential to describe and validate new biomarkers and/or therapeutic targets responsible for lung vascularisation and/or angiogenesis. CD146 is an endothelial cell adhesion molecule also expressed on mesenchymal stem cells, epithelial cells and T-helper 17 lymphocytes. A soluble form of CD146 exists, sCD146, which can be detected in blood and biological samples, including the bronchoalveolar lavage fluid. CD146/sCD146 are involved in angiogenesis and inflammation and are associated with many inflammatory diseases. Recent studies have reported both protective and detrimental roles of CD146/sCD146 in lung diseases. In the present review, we will describe the potential role of CD146 and sCD146 in the pathogenesis of respiratory diseases in order to use them as key mechanistic biomarkers or new therapeutical targets to treat or even cure these pathologies.

Connective tissue disease-associated interstitial lung disease is one of the most common subtypes of interstitial lung disease, which is a leading cause of morbidity and mortality in patients with these systemic autoimmune rheumatic diseases. A spectrum of disease trajectories exists within individual and across different connective tissue diseases. In individuals with connective tissue diseases who are at risk or at the early asymptomatic stage with interstitial lung changes, we have potential windows of opportunity for interventions to prevent the development of or progression to interstitial lung disease. In this perspective, we use systemic sclerosis and rheumatoid arthritis as sample cases to discuss emerging knowledge on disease pathogenesis, as well as to apply the preventative medicine concept for pharmacotherapeutic approaches at different disease stages of connective tissue disease-associated interstitial lung disease.

Chronic lung diseases such as COPD, asthma, idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension are characterised by aberrant remodelling and degradation of the extracellular matrix. This is particularly evident within the basement membrane. Collagen IV, a major component of the basement membrane, is essential for maintaining structural support and regulating cell behaviour. However, disruptions in collagen IV metabolism and basement membrane integrity have been implicated in the pathogenesis of chronic lung diseases, especially in ageing populations where basement membrane turnover is compromised. Cleavage of collagen IV during basement membrane remodelling generates bioactive fragments known as matrikines, which serve as markers of tissue remodelling and potential diagnostic biomarkers. Despite the prominence of collagen IV in the basement membrane, its role in chronic lung diseases remains understudied compared to other collagen types. This review provides a comprehensive exploration of the roles of basement membrane collagen IV and its matrikines in COPD, asthma, IPF and pulmonary hypertension, emphasising their significance beyond classical matrix components. Through an analysis of clinical studies, animal models and in vitro experiments, the contributions of collagen IV to disease pathogenesis and progression are discussed. Furthermore, potential diagnostic and therapeutic implications of targeting collagen IV are outlined. By providing insights into the relationship between collagen IV and chronic lung diseases, this review aims to guide future research and clinical interventions in the field.

Ageing significantly impacts lung function and increases susceptibility to chronic lung diseases. The lung is a complex organ with multiple cell types that undergo cellular age-related perturbations or hallmarks. As knowledge of ageing mechanisms has progressed, we have a better understanding how intracellular adaptations impact cellular crosstalk and integrate to increase the susceptibility to age-related diseases in the lung. Herein, we discuss the prospects of exhaustion of lung progenitor cells, disrupted lung cell plasticity, perturbation in fibroblasts, impaired adaptive immune responses and alterations in lung microenvironment in the promotion of ageing and age-related lung diseases. Additionally, the ageing process trajectory of the lung depends on a combination of biological, genetic, metabolic, biomechanical and sociobehavioural factors that range from protective phenotypes to accelerated ageing phenotypes. We propose the concept of AgEnOmics, which expands the temporal dimension of lung ageing by distinguishing between chronological ageing and accelerated lung ageing phenotypes. Based on this concept, we define biomarkers of biological ageing that will help to define accelerated ageing and early interventions in biological ageing-related lung diseases.

Conventional silicone airway stents are effective in relieving stenoses but are prone to complications such as migration and granulation tissue formation. These complications reduce patients' tolerance and induce unwanted procedures, limiting their overall benefit. Over the past decade, personalised, three-dimensional (3D)-printed silicone stents have emerged as a possible solution to some of these concerns. In this narrative review, the authors aim to guide the physician into understanding the relatively straightforward creative process behind 3D stents and the selection process of the best patients for their use. Current use is limited to complex anatomical airway stenoses, but more indications could blossom from future trials as technology, expertise and access develop going forward.

Background: Long-term survivors of pulmonary embolism (PE) exhibit decreased exercise capacity, dyspnoea and a diminished quality of life. Exercise may represent a beneficial strategy for ameliorating persistent symptoms following PE.

Research question: Is exercise training beneficial for improving exercise capacity and quality of life in patients with PE? Additionally, is it safe and feasible?

Study design and methods: The aim of this systematic review was to evaluate the safety, feasibility and efficacy of exercise training in improving exercise capacity and quality of life in patients with PE. In order to comprehensively assess the available evidence, we conducted a systematic review using a combination of free-text terms and medical subject headings according to database requirements in PubMed, Medline, Web of Science, Scopus, Embase and the Cochrane Library from inception until 17 September 2024.

Results: We included a total of nine trials including 583 patients, including 391 in the interventional group and 190 in the control group. The difference in the average adverse event rates between the exercise group (0.5%) and the control group (0%) was not significant. The overall recruitment rate was approximately 51% (range: 38-65%), the withdrawal rate was approximately 5% (range: 0-13%) and the adherence rate was 87% (range: 61-100%). The studies reported average improvements in peak oxygen consumption (exercise group: 7.55 mL·kg^-1·min^-1; control group: 1.95 mL·kg^-1·min^-1), incremental shuttle walk test distance (exercise group: 142 m; control group: 69.5 m), vitality scores (exercise group: 13.95; control group: 3.95), and role emotional scores (exercise group: 12.05; control group: -0.1). However, due to considerable discrepancies in the scoring systems, an average improvement in Pulmonary Embolism Quality of Life questionnaire score could not be determined. Notably, no improvement in dyspnoea was reported.

Conclusion: This systematic review indicates that exercise training seems to be safe and feasible for patients with PE. It appears to enhance patients' exercise capacity and quality of life, although its impact on alleviating dyspnoea remains limited. However, given the absence of large-scale randomised controlled trials, these findings should be interpreted with caution.