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Lung Feb 2024In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe.... (Review)
Review
In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored.
Topics: Humans; Chronic Cough; Chronic Disease; Cough; Antitussive Agents; Europe
PubMed: 38127133
DOI: 10.1007/s00408-023-00666-y -
Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids.Life Science Alliance Aug 2023Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target...
Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.
Topics: Humans; Alveolar Epithelial Cells; Lung; Idiopathic Pulmonary Fibrosis; Fibrosis; Pluripotent Stem Cells; Organoids
PubMed: 37230801
DOI: 10.26508/lsa.202201853 -
The Journal of Clinical Investigation Jul 2023Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and... (Review)
Review
Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and impairs pulmonary function. CD4+FOXP3+ regulatory T cells (Tregs) interact with cells of both the innate and the adaptive immune system to limit acute pulmonary inflammation and promote its resolution. Tregs also provide tissue protection and coordinate lung tissue repair, facilitating a return to homeostatic pulmonary function. Here, we review Treg-mediated modulation of the host response to respiratory pathogens, focusing on mechanisms underlying how Tregs promote resolution of inflammation and repair of acute lung injury. We also discuss potential strategies to harness and optimize Tregs as a cellular therapy for patients with severe acute respiratory infection and discuss open questions in the field.
Topics: Humans; T-Lymphocytes, Regulatory; Lung; Acute Lung Injury; Pneumonia; Inflammation; Forkhead Transcription Factors
PubMed: 37463441
DOI: 10.1172/JCI170505 -
Nature Communications Dec 2023The spread of many infectious diseases relies on aerosol transmission to the respiratory tract. Here we design an intranasal mask comprising a positively-charged...
The spread of many infectious diseases relies on aerosol transmission to the respiratory tract. Here we design an intranasal mask comprising a positively-charged thermosensitive hydrogel and cell-derived micro-sized vesicles with a specific viral receptor. We show that the positively charged hydrogel intercepts negatively charged viral aerosols, while the viral receptor on vesicles mediates the entrapment of viruses for inactivation. We demonstrate that when displaying matched viral receptors, the intranasal masks protect the nasal cavity and lung of mice from either severe acute respiratory syndrome coronavirus 2 or influenza A virus. With computerized tomography images of human nasal cavity, we further conduct computational fluid dynamics simulation and three-dimensional printing of an anatomically accurate human nasal cavity, which is connected to human lung organoids to generate a human respiratory tract model. Both simulative and experimental results support the suitability of intranasal masks in humans, as the likelihood of viral respiratory infections induced by different variant strains is dramatically reduced.
Topics: Humans; Animals; Mice; Respiratory Aerosols and Droplets; Respiratory System; Administration, Intranasal; Virus Diseases; Hydrogels; Aerosols
PubMed: 38110357
DOI: 10.1038/s41467-023-44134-w -
The Journal of Allergy and Clinical... Sep 2023Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts...
BACKGROUND
Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice.
OBJECTIVES
This study sought to begin identifying farm-derived asthma-protective agents.
METHODS
Our work unfolded along 2 unbiased and independent but complementary discovery paths. Dust extracts (DEs) from protective and nonprotective farms (European and Amish cowsheds vs European sheep sheds) were analyzed by comparative nuclear magnetic resonance profiling and differential proteomics. Bioactivity-guided size fractionation focused on protective Amish cowshed DEs. Multiple in vitro and in vivo functional assays were used in both paths. Some of the proteins thus identified were characterized by in-solution and in-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzymatic digestion/peptide mapping followed by liquid chromatography/mass spectrometry. The cargo carried by these proteins was analyzed by untargeted liquid chromatography-high-resolution mass spectrometry.
RESULTS
Twelve carrier proteins of animal and plant origin, including the bovine lipocalins Bos d 2 and odorant binding protein, were enriched in DEs from protective European cowsheds. A potent asthma-protective fraction of Amish cowshed DEs (≈0.5% of the total carbon content of unfractionated extracts) contained 7 animal and plant proteins, including Bos d 2 and odorant binding protein loaded with fatty acid metabolites from plants, bacteria, and fungi.
CONCLUSIONS
Animals and plants from traditional farms produce proteins that transport hydrophobic microbial and plant metabolites. When delivered to mucosal surfaces, these agents might regulate airway responses.
Topics: Female; Animals; Cattle; Mice; Sheep; Farms; Dust; Asthma; Allergens; Respiratory System
PubMed: 37271318
DOI: 10.1016/j.jaci.2023.05.013 -
Paediatric Respiratory Reviews Sep 2023Airway clearance is a critical component of both maintenance of respiratory health and management of acute respiratory illnesses. The process of effective airway... (Review)
Review
Airway clearance is a critical component of both maintenance of respiratory health and management of acute respiratory illnesses. The process of effective airway clearance begins with the recognition of secretions in the airway and culminates in expectoration or swallowing. There are multiple points on this continuum at which neuromuscular disease causes impaired airway clearance. This can result in an otherwise mild upper respiratory illness progressing unabated from an easily managed condition to a severe, life-threatening lower respiratory illness requiring intensive therapy for patient recovery. Even during periods of relative health, airway protective mechanisms can be compromised, and patients may have difficulty managing average quantities of secretions. This review summarizes airway clearance physiology and pathophysiology, mechanical and pharmacologic treatment modalities, and provides a practical approach for managing secretions in patients with neuromuscular disease. Neuromuscular disease is an umbrella term used to describe disorders that involve dysfunction of peripheral nerves, the neuromuscular junction, or skeletal muscle. Although this paper specifically reviews airway clearance pertaining to those with neuromuscular diseases (e.g., muscular dystrophy, spinal muscular atrophy, myasthenia gravis), most of its content is relevant to the management of patients with central nervous system disorders such as chronic static encephalopathy caused by trauma, metabolic or genetic abnormalities, congenital infection, or neonatal hypoxic-ischemic injury.
Topics: Infant, Newborn; Humans; Neuromuscular Diseases; Respiratory System
PubMed: 36894356
DOI: 10.1016/j.prrv.2023.02.002 -
Frontiers in Cellular and Infection... 2024Pulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of... (Review)
Review
Pulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of fibroblasts, excessive deposition of extracellular matrix (ECM), and concomitant inflammatory damage. Its characteristics include short median survival, high mortality rate, and limited treatment effectiveness. More in-depth studies on the mechanisms of PF are needed to provide better treatment options. The idea of the gut-lung axis has emerged as a result of comprehensive investigations into the microbiome, metabolome, and immune system. This theory is based on the material basis of microorganisms and their metabolites, while the gut-lung circulatory system and the shared mucosal immune system act as the connectors that facilitate the interplay between the gastrointestinal and respiratory systems. The emergence of a new view of the gut-lung axis is complementary and cross-cutting to the study of the mechanisms involved in PF and provides new ideas for its treatment. This article reviews the mechanisms involved in PF, the gut-lung axis theory, and the correlation between the two. Exploring the gut-lung axis mechanism and treatments related to PF from the perspectives of microorganisms, microbial metabolites, and the immune system. The study of the gut-lung axis and PF is still in its early stages. This review systematically summarizes the mechanisms of PF related to the gut-lung axis, providing ideas for subsequent research and treatment of related mechanisms.
Topics: Humans; Pulmonary Fibrosis; Alveolar Epithelial Cells; Extracellular Matrix; Fibroblasts; Metabolome; Lung
PubMed: 38362497
DOI: 10.3389/fcimb.2024.1258246 -
Current Opinion in Virology Aug 2023To cause pandemics, zoonotic respiratory viruses need to adapt to replication in and spread between humans, either via (indirect or direct) contact or through the air... (Review)
Review
To cause pandemics, zoonotic respiratory viruses need to adapt to replication in and spread between humans, either via (indirect or direct) contact or through the air via droplets and aerosols. To render influenza A viruses transmissible via air, three phenotypic viral properties must change, of which receptor-binding specificity and polymerase activity have been well studied. However, the third adaptive property, hemagglutinin (HA) acid stability, is less understood. Recent studies show that there may be a correlation between HA acid stability and virus survival in the air, suggesting that a premature conformational change of HA, triggered by low pH in the airways or droplets, may render viruses noninfectious before they can reach a new host. We here summarize available data from (animal) studies on the impact of HA acid stability on airborne transmission and hypothesize that the transmissibility of other respiratory viruses may also be impacted by an acidic environment in the airways.
Topics: Humans; Animals; Influenza A virus; Hemagglutinins; Hemagglutinin Glycoproteins, Influenza Virus; Respiratory System; Adaptation, Physiological; Influenza, Human; Orthomyxoviridae Infections
PubMed: 37307646
DOI: 10.1016/j.coviro.2023.101335 -
Respirology (Carlton, Vic.) Aug 2023For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience... (Review)
Review
For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience exacerbations, may require systemic corticosteroids (SCSs) to maintain asthma control. Although SCS are highly effective in this regard, even modest exposure to these medications can increase the risk for long-term, adverse health outcomes, such as type 2 diabetes, renal impairment, cardiovascular disease and overall mortality. Clinical and real-world data from studies investigating asthma severity, control and treatment practices around the globe have suggested that SCS are overused in asthma management, adding to the already substantial healthcare burden experienced by patients. Throughout Asia, although data on asthma severity, control and SCS usage are limited and vary widely among countries, available data strongly suggest a pattern of overuse consistent with the broader global trend. Coordinated changes at the patient, provider, institutional and policy levels, such as increasing disease awareness, promoting better adherence to treatment guidelines and increasing availability of safe and effective alternatives to SCS, are likely necessary to reduce the SCS burden for patients with asthma in Asia.
Topics: Humans; Diabetes Mellitus, Type 2; Asthma; Adrenal Cortex Hormones; Asia; Anti-Asthmatic Agents
PubMed: 37301540
DOI: 10.1111/resp.14533 -
A novel method for assessment of airway opening pressure without the need for low-flow insufflation.Critical Care (London, England) Jul 2023Airway opening pressure (AOP) detection and measurement are essential for assessing respiratory mechanics and adapting ventilation. We propose a novel approach for AOP...
BACKGROUND
Airway opening pressure (AOP) detection and measurement are essential for assessing respiratory mechanics and adapting ventilation. We propose a novel approach for AOP assessment during volume assist control ventilation at a usual constant-flow rate of 60 L/min.
OBJECTIVES
To validate the conductive pressure (P) method, which compare the P-defined on the airway pressure waveform as the difference between the airway pressure level at which an abrupt change in slope occurs at the beginning of insufflation and PEEP-to resistive pressure for AOP detection and measurement, and to compare its respiratory and hemodynamic tolerance to the standard low-flow insufflation method.
METHODS
The proof-of-concept of the P method was assessed on mechanical (lung simulator) and physiological (cadavers) bench models. Its diagnostic performance was evaluated in 213 patients, using the standard low-flow insufflation method as a reference. In 45 patients, the respiratory and hemodynamic tolerance of the P method was compared with the standard low-flow method.
MEASUREMENTS AND MAIN RESULTS
Bench assessments validated the P method proof-of-concept. Sensitivity and specificity of the P method for AOP detection were 93% and 91%, respectively. AOP obtained by P and standard low-flow methods strongly correlated (r = 0.84, p < 0.001). Changes in SpO were significantly lower during P than during standard method (p < 0.001).
CONCLUSION
Determination of P during constant-flow assist control ventilation may permit to easily and safely detect and measure AOP.
Topics: Humans; Insufflation; Lung; Respiratory Physiological Phenomena; Respiratory Mechanics; Respiration, Artificial
PubMed: 37420282
DOI: 10.1186/s13054-023-04560-0