Neutrophils and NETs in modulating acute and chronic inflammation

Blood, Journal Year: 2019, Volume and Issue: 133(20), P. 2178 - 2185

Published: March 22, 2019

Language: Английский

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Future therapies for cystic fibrosis

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 8, 2023

Abstract We are currently witnessing transformative change for people with cystic fibrosis the introduction of small molecule, mutation-specific drugs capable restoring function defective protein, transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there multiple fibrosis-causing genetic variants; not suitable all variants and also do correct multisystem clinical manifestations disease. For many, will remain need improved treatments. Those patients responsive to CFTR modulators may have found these therapies be transformational; research is now focusing on safely reducing burden symptom-directed treatment. available in parts globe, an issue which further widening existing health inequalities. who for- or access to- modulator drugs, alternative approaches progressing through trials pipeline. There challenges encountered design implementation trials, established global CF infrastructure major advantage. Here, Cystic Fibrosis National Research Strategy Group UK NIHR Respiratory Translational Collaboration looks future consider priorities development.

Language: Английский

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Cystic fibrosis

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 8, 2024

Language: Английский

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GC-MS-based metabolomics of volatile organic compounds in exhaled breath: applications in health and disease. A review

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 10

Published: Jan. 8, 2024

Exhaled breath analysis, with particular emphasis on volatile organic compounds, represents a growing area of clinical research due to its obvious advantages over other diagnostic tests. Numerous pathologies have been extensively investigated for the identification specific biomarkers in exhalates through metabolomics. However, transference tests clinics remains limited, mainly deficiency methodological standardization. Critical steps include selection sample types, collection devices, and enrichment techniques. GC-MS is reference analytical technique analysis compounds exhalates, especially during biomarker discovery phase This review comprehensively examines compares metabolomic studies focusing cancer, lung diseases, infectious diseases. In addition delving into experimental designs reported, it also provides critical discussion aspects, ranging from design potential pathology-specific biomarkers.

Language: Английский

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Help, hinder, hide and harm: what can we learn from the interactions between Pseudomonas aeruginosa and Staphylococcus aureus during respiratory infections?

Thorax, Journal Year: 2019, Volume and Issue: 74(7), P. 684 - 692

Published: Feb. 18, 2019

Recent studies of human respiratory secretions using culture-independent techniques have found a surprisingly diverse array microbes. Interactions among these community members can profoundly impact microbial survival, persistence and antibiotic susceptibility and, consequently, disease progression. Studies polymicrobial interactions in the microbiota shown that taxonomic structural compositions, resulting behaviours, communities differ substantially from those individual constituent species ways clinical importance. These primarily involved oral gastrointestinal microbiomes. While field is relatively young, early findings suggest tract also compete cooperate may influence outcomes. Ongoing efforts therefore focus on how inform more ‘enlightened’, rational approaches to combat infections. Among most common diseases involving infections are cystic fibrosis (CF), non-CF bronchiectasis, COPD ventilator-associated pneumonia. be diverse, two best-studied Staphylococcus aureus Pseudomonas aeruginosa , which exhibit range competitive cooperative interactions. Here, we review state research pulmonary coinfection with pathogens, including their prevalence, combined independent associations patient outcomes, mechanisms could lung health. Because P. aeruginosa–S. well studied CF, this serves as paradigm for our discussions organisms recommendations future disease.

Language: Английский

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Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

Genes, Journal Year: 2019, Volume and Issue: 10(3), P. 183 - 183

Published: Feb. 26, 2019

Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection their lung. The inflammatory response progressively increases children that include both upper and lower airways. Infectious leads an increase mucus viscosity plugging small medium-size bronchioles. Eventually, neutrophils chronically infiltrate airways biofilm or chronic bacterial infection. Perpetual airway inflammation destroy lungs, which increased morbidity eventual mortality most patients Studies have now established cytotoxins, extracellular DNA, traps (NETs) are associated clogging lung injury In addition opportunistic pathogens, various aspects CF milieux (e.g., pH, salt concentration, phenotypes) influence NETotic capacity neutrophils. milieu may promote survival pro-inflammatory aberrant NETosis, rather than anti-inflammatory apoptotic death these cells. Degrading NETs helps manage disease; since DNAse treatment release cytotoxins from NETs, further improvements needed degrade maximal positive effects. Neutrophil-T cell interactions be important regulating viral infection-mediated pulmonary exacerbations infections. Therefore, clarifying role disease identifying therapies preserve effects neutrophils, while reducing detrimental cytotoxic components, essential achieving innovative therapeutic advances.

Language: Английский

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Lipid–Protein and Protein–Protein Interactions in the Pulmonary Surfactant System and Their Role in Lung Homeostasis

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(10), P. 3708 - 3708

Published: May 25, 2020

Pulmonary surfactant is a lipid/protein complex synthesized by the alveolar epithelium and secreted into airspaces, where it coats protects large respiratory air–liquid interface. Surfactant, assembled as network of membranous structures, integrates elements in charge reducing surface tension to minimum along breathing cycle, thus maintaining open gas exchange also protecting lung body from entrance myriad potentially pathogenic entities. Different molecules establish multivalent crosstalk with epithelium, immune system microbiota, constituting crucial platform sustain homeostasis, under health disease. This review summarizes some most important interactions within how multiple lipid–protein protein–protein contribute proper maintenance an operative surface.

Language: Английский

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Specific Inhibition of the NLRP3 Inflammasome as an Antiinflammatory Strategy in Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2019, Volume and Issue: 200(11), P. 1381 - 1391

Published: Aug. 27, 2019

Rationale: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective antiinflammatory therapies for people CF (PWCF) represents a significant challenge.Objectives: To identify altered immunometabolism in the neutrophil investigate feasibility specific inhibition NLRP3 (NOD-, LRR-, pyrin domain–containing protein 3) inflammasome as strategy vivo.Methods: Key markers increased aerobic glycolysis, known Warburg effect, including cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, succinate, HIF-1α (hypoxia-inducible factor-1α), lactate, IL-1β precursor pro–IL-1β, well caspase-1 activity processing pro–IL-1β to inflammasome, were measured neutrophils from blood airway secretions healthy control subjects (n = 12), PWCF 16), after double-lung transplantation 6). effects on inflammation bacterial clearance murine model subsequently assessed vivo.Measurements Main Results: display glycolysis systemic circulation. This effect driven low-level endotoxemia, unaffected CFTR (cystic transmembrane conductance regulator) modulation, resolves transplant. produced processed its mature active form LPS-rich lung via caspase-1. Specific vivo MCC950 inhibited lungs mice (P < 0.0001), resulting significantly reduced improved 0.0001).Conclusions: response may have an anti-infective role CF.

Language: Английский

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CFTR Protein: Not Just a Chloride Channel?

Cells, Journal Year: 2021, Volume and Issue: 10(11), P. 2844 - 2844

Published: Oct. 22, 2021

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in gene encoding protein called Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR known to acts as chloride (Cl-) channel expressed the exocrine glands of several body systems where it also regulates other ion channels, including epithelial sodium (Na+) (ENaC) that plays key role salt absorption. This function crucial osmotic balance mucus and its viscosity. However, pathophysiology CF more challenging than mere dysregulation transport, mainly resulting impaired mucociliary clearance (MCC) with consecutive bronchiectasis pancreatic insufficiency. review shows not just channel. For long time, research has focused on abnormal Cl- Na+ transport. Yet, numerous pathways, such transport HCO3-, glutathione thiocyanate, immune cells, metabolism lipids. It influences pH homeostasis airway surface liquid thus MCC well innate immunity leading chronic infection inflammation, all which are considered pathophysiological characteristics CF.

Language: Английский

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Macrophage metabolic reprogramming during chronic lung disease

Mucosal Immunology, Journal Year: 2020, Volume and Issue: 14(2), P. 282 - 295

Published: Nov. 12, 2020

Airway macrophages (AMs) play key roles in the maintenance of lung immune tolerance. Tissue tailored, highly specialised and strategically positioned, AMs are critical sentinels homoeostasis. In last decade, there has been a revolution our understanding how metabolism underlies macrophage functions. While these initial observations were made during steady state or using vitro polarised macrophages, recent studies have indicated that many chronic diseases (CLDs), adapt their metabolic profile to fit local niche. By generating reactive oxygen species (ROS) for pathogen defence, utilising aerobic glycolysis rapidly generate cytokines, employing mitochondrial respiration fuel inflammatory responses, utilise reprogramming host although changes may also support pathology. This review focuses on alterations underlie AM phenotype function CLDs. Particular emphasis is given new plasticity be exploited develop AM-focused therapies.

Language: Английский

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