Role of Neutrophils in Cystic Fibrosis Lung Disease

Conese, Massimo; Castellani, Stefano; D’Oria, Susanna; Gioia, Sante Di; Montemurro, P.

doi:10.5772/67798

Cited by 5 publications

(7 citation statements)

References 142 publications

(146 reference statements)

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“…The main culprit for this effect is represented by proteases secreted by neutrophils themselves. Neutrophil elastase (NE) has several potential roles in disabling neutrophils including cleavage of opsonophagocytosis proteins, such as iC3b, complement receptor 1 (CR1) and C5a receptor, the chemokine receptor CXR1, and TIM3 receptor leading to decreased galectin 9/TIM3 interactions [30]. Overall, the loss of these proteins is responsible for suboptimal local neutrophil priming and bacterial clearance.…”

Section: The Inflammatory Response In Cf Airwaysmentioning

confidence: 99%

Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

Castellani

Gioia

Toma

et al. 2018

Analytical Cellular Pathology

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Chronic inflammation, oxidative stress, mucus plugging, airway remodeling, and respiratory infections are the hallmarks of the cystic fibrosis (CF) lung disease. The airway epithelium is central in the innate immune responses to pathogens colonizing the airways, since it is involved in mucociliary clearance, senses the presence of pathogens, elicits an inflammatory response, orchestrates adaptive immunity, and activates mesenchymal cells. In this review, we focus on cellular models of the human CF airway epithelium that have been used for studying mucus production, inflammatory response, and airway remodeling, with particular reference to two- and three-dimensional cultures that better recapitulate the native airway epithelium. Cocultures of airway epithelial cells, macrophages, dendritic cells, and fibroblasts are instrumental in disease modeling, drug discovery, and identification of novel therapeutic targets. Nevertheless, they have to be implemented in the CF field yet. Finally, novel systems hijacking on tissue engineering, including three-dimensional cocultures, decellularized lungs, microfluidic devices, and lung organoids formed in bioreactors, will lead the generation of relevant human preclinical respiratory models a step forward.

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Section: The Inflammatory Response In Cf Airwaysmentioning

confidence: 99%

Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

Castellani

Gioia

Toma

et al. 2018

Analytical Cellular Pathology

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“…The uncontrolled release of these enzymes causes lung tissue damage and severe airway inflammation. We have shown that P. aeruginosa LPS-induced MPO levels can be reduced by treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), plausibly by restoring the trafficking of ΔF508-CFTR, suggesting that a functional CFTR is required to keep a tab on uncontrolled neutrophil activation [ 172 ]. Mechanistically, an absence or dysfunction of CFTR in neutrophils results in the deactivation of the guanosine triphosphate (GTP)-binding protein Rab27a, which causes impaired granule exocytosis [ 168 , 172 ].…”

Section: Autophagy-mediated Cftr and Immune Response Dysfunctionmentioning

confidence: 99%

“…We have shown that P. aeruginosa LPS-induced MPO levels can be reduced by treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), plausibly by restoring the trafficking of ΔF508-CFTR, suggesting that a functional CFTR is required to keep a tab on uncontrolled neutrophil activation [ 172 ]. Mechanistically, an absence or dysfunction of CFTR in neutrophils results in the deactivation of the guanosine triphosphate (GTP)-binding protein Rab27a, which causes impaired granule exocytosis [ 168 , 172 ]. Several studies now agree that the pharmacological inhibition of CFTR or the mutant ΔF508-CFTR is sufficient to cause deregulated neutrophil activation via the activation of the NFκB pathway, resulting in hyperinflammation [ 172 ].…”

Section: Autophagy-mediated Cftr and Immune Response Dysfunctionmentioning

confidence: 99%

“…Mechanistically, an absence or dysfunction of CFTR in neutrophils results in the deactivation of the guanosine triphosphate (GTP)-binding protein Rab27a, which causes impaired granule exocytosis [ 168 , 172 ]. Several studies now agree that the pharmacological inhibition of CFTR or the mutant ΔF508-CFTR is sufficient to cause deregulated neutrophil activation via the activation of the NFκB pathway, resulting in hyperinflammation [ 172 ].…”

Section: Autophagy-mediated Cftr and Immune Response Dysfunctionmentioning

confidence: 99%

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Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations

Pehote

Vij

2020

Cells

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The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy–lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.

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“…Each of these mediators produce an amplification of the inflammatory response due to generation of more neutrophils and their recruitment and activation. The end-stage disease is determined by damage to bronchial walls by neutrophil-derived reactive oxygen species (ROS) and proteases [5].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells

Laselva

Allegretta

Gioia

et al. 2021

Cells

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Cystic Fibrosis (CF) is caused by mutations on the CF transmembrane conductance regulator (CFTR) gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early oxidative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stimulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/H2O2 and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Finally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy.

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Role of Neutrophils in Cystic Fibrosis Lung Disease

Cited by 5 publications

References 142 publications

Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations

Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells

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