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Seminars in Immunopathology Feb 2020Worldwide 300 million children and adults are affected by asthma. The development of asthma is influenced by environmental and other exogenous factors synergizing with... (Review)
Review
Worldwide 300 million children and adults are affected by asthma. The development of asthma is influenced by environmental and other exogenous factors synergizing with genetic predisposition, and shaping the lung microbiome especially during birth and in very early life. The healthy lung microbial composition is characterized by a prevalence of bacteria belonging to the phyla Bacteroidetes, Actinobacteria, and Firmicutes. However, viral respiratory infections are associated with an abundance of Proteobacteria with genera Haemophilus and Moraxella in young children and adult asthmatics. This dysbiosis supports the activation of inflammatory pathways and contributes to bronchoconstriction and bronchial hyperresponsiveness. Exogenous factors can affect the natural lung microbiota composition positively (farming environment) or negatively (allergens, air pollutants). It is evident that also gut microbiota dysbiosis has a high influence on asthma pathogenesis. Antibiotics, antiulcer medications, and other drugs severely impair gut as well as lung microbiota. Resulting dysbiosis and reduced microbial diversity dysregulate the bidirectional crosstalk across the gut-lung axis, resulting in hypersensitivity and hyperreactivity to respiratory and food allergens. Efforts are undertaken to reconstitute the microbiota and immune balance by probiotics and engineered bacteria, but results from human studies do not yet support their efficacy in asthma prevention or treatment. Overall, dysbiosis of gut and lung seem to be critical causes of the increased emergence of asthma.
Topics: Adult; Asthma; Child; Child, Preschool; Dysbiosis; Gastrointestinal Microbiome; Humans; Lung; Microbiota
PubMed: 32072252
DOI: 10.1007/s00281-019-00775-y -
Allergy Feb 2023The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and... (Review)
Review
The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.
Topics: Humans; Cytokines; Alarmins; Interleukin-33; Interleukin-1 Receptor-Like 1 Protein; Asthma; Thymic Stromal Lymphopoietin; Inflammation
PubMed: 36463491
DOI: 10.1111/all.15609 -
Nature Jun 2022The sympathetic and parasympathetic nervous systems regulate the activities of internal organs, but the molecular and functional diversity of their constituent neurons...
The sympathetic and parasympathetic nervous systems regulate the activities of internal organs, but the molecular and functional diversity of their constituent neurons and circuits remains largely unknown. Here we use retrograde neuronal tracing, single-cell RNA sequencing, optogenetics and physiological experiments to dissect the cardiac parasympathetic control circuit in mice. We show that cardiac-innervating neurons in the brainstem nucleus ambiguus (Amb) are comprised of two molecularly, anatomically and functionally distinct subtypes. The first, which we call ambiguus cardiovascular (ACV) neurons (approximately 35 neurons per Amb), define the classical cardiac parasympathetic circuit. They selectively innervate a subset of cardiac parasympathetic ganglion neurons and mediate the baroreceptor reflex, slowing heart rate and atrioventricular node conduction in response to increased blood pressure. The other, ambiguus cardiopulmonary (ACP) neurons (approximately 15 neurons per Amb) innervate cardiac ganglion neurons intermingled with and functionally indistinguishable from those innervated by ACV neurons. ACP neurons also innervate most or all lung parasympathetic ganglion neurons-clonal labelling shows that individual ACP neurons innervate both organs. ACP neurons mediate the dive reflex, the simultaneous bradycardia and bronchoconstriction that follows water immersion. Thus, parasympathetic control of the heart is organized into two parallel circuits, one that selectively controls cardiac function (ACV circuit) and another that coordinates cardiac and pulmonary function (ACP circuit). This new understanding of cardiac control has implications for treating cardiac and pulmonary diseases and for elucidating the control and coordination circuits of other organs.
Topics: Animals; Cardiovascular System; Heart; Lung; Medulla Oblongata; Mice; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Optogenetics; Parasympathetic Nervous System; RNA-Seq; Single-Cell Analysis
PubMed: 35650438
DOI: 10.1038/s41586-022-04760-8 -
A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.Nature Cell Biology Feb 2023The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell...
The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.
Topics: Humans; Cell Differentiation; Embryo, Mammalian; Gene Expression Profiling; Lung; Stem Cells
PubMed: 36646791
DOI: 10.1038/s41556-022-01064-x -
The European Respiratory Journal Mar 2023Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma.
METHODS
This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV) during the late asthmatic response (LAR) measured by area under the curve (AUC) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide ( ) were secondary and exploratory end-points.
RESULTS
28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC (p=0.097) and EAR% (p=0.105). levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated.
CONCLUSION
Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.
Topics: Humans; Administration, Inhalation; Allergens; Asthma; Bronchial Provocation Tests; Cross-Over Studies; Cytokines; Double-Blind Method; Forced Expiratory Volume; Hypersensitivity, Immediate; Immunoglobulin Fragments; Sputum; Thymic Stromal Lymphopoietin; Adolescent; Young Adult; Adult; Middle Aged
PubMed: 36822634
DOI: 10.1183/13993003.01193-2022 -
Frontiers in Medicine 2021Exercise-induced bronchoconstriction (EIB) is a transient airflow obstruction, typically 5-15 min after physical activity. The pathophysiology of EIB is related to the... (Review)
Review
Exercise-induced bronchoconstriction (EIB) is a transient airflow obstruction, typically 5-15 min after physical activity. The pathophysiology of EIB is related to the thermal and osmotic changes of the bronchial mucosa, which cause the release of mediators and the development of bronchoconstriction in the airways. EIB in children often causes an important limitation to physical activities and sports. However, by taking appropriate precautions and through adequate pharmacological control of the condition, routine exercise is extremely safe in children. This review aims to raise awareness of EIB by proposing an update, based on the latest studies, on pathological mechanisms, diagnosis, and therapeutic approaches in children.
PubMed: 35047536
DOI: 10.3389/fmed.2021.814976