Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

Chandler, Joshua D.; Margaroli, Camilla; Horati, Hamed; Kilgore, Matthew B.; Veltman, Mieke; Liu, H. Ken; Taurone, Alexander; Peng, Limin; Guglani, Lokesh; Uppal, Karan; Go, Young‐Mi; Tiddens, Harm A.W.M.; Scholte, Bob J.; Tirouvanziam, Rabindra; Jones, Dean P.; Janssens, Hettie M.

doi:10.1183/13993003.01118-2018

Cited by 45 publications

(38 citation statements)

References 49 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NET presence was found to be elevated in acute respiratory distress syndrome (ARDS) patients with ventilator-associated pneumonia compared to ARDS alone, and correlated with both bacterial burden and CXCL8 [81]. Considering that MPO has been found to be elevated in the airways of ARDS patients [82] and that this enzyme is associated with lung damage in CF [83,84], NET-associated MPO may be a contributing factor in progression of disease in ARDS. Studies of NETosis are also contributing to a better understanding of neutrophil plasticity.…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Giacalone

Margaroli

Mall

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI).

show abstract

Section: Bacterial Infectionsmentioning

confidence: 99%

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Giacalone

Margaroli

Mall

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Before the discovery of NETosis (controlled neutrophil cell death with the release of NETs), necrosis was generally considered to be the primary source of neutrophil DNA in the lungs of patients with CF; however, this was subsequently revealed not to be the case, as NETosis was shown to be responsible for the release of myeloperoxidase (MPO), heparin-binding protein (HBP), DNA and NE in CF sputum and bronchoalveolar lavage fluid (BALF) [132][133][134][135]. As the high concentration of inflammatory markers and these proteins, both in the CF sputum and BALF, correlates with decreasing lung function, NETosis plays an essential role in the pathogenesis of CF [132,134,[136][137][138][139][140][141][142][143][144][145][146]. The raised levels of NE and cathepsin G have been suggested to be responsible for increased levels of peptides and amino acids in sputum samples, whilst the raised concentrations of these peptides and amino acids correlate with increased frequency of P. aeruginosa infection in the lungs of patients with CF [147].…”

Section: Neutrophilsmentioning

confidence: 99%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

show abstract

“…Infiltrated neutrophils either phagocytose microbial pathogens and generate reactive oxygen species (ROS) for intracellular killing, or degranulate to release cytotoxic peptides for extracellular killing, or cast NETs as a DNA-mesh to ensnare microbial pathogens [26,27,28]. During NETosis, neutrophils release, decondensed chromatin coated with elastase, myeloperoxidase (MPO), and other cytotoxic granular proteases [12,27,29,30,31,32]. These neutrophil components perpetuate severe inflammation that characterizes CF lung disease [10,11,31,33,34,35].…”

Section: Introductionmentioning

confidence: 99%

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

Khan

Ali

Sweezey

et al. 2019

Genes

View full text Add to dashboard Cite

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

show abstract

Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

Cited by 45 publications

References 49 publications

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

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

Contact Info

Product

Resources

About