Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

Lavelle, Gillian M.; White, Mark; Browne, Niall; McElvaney, Noel G.; Reeves, Emer P.

doi:10.1155/2016/5258727

Cited by 93 publications

(93 citation statements)

References 117 publications

(201 reference statements)

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“…Although murine models of CF do not recapitulate the clinical manifestations of CF lung disease, CF mice manifest an inflammatory lung phenotype coupled to hyper-responsiveness to bacteria or microbial products and are widely used to test candidate drugs and their mechanism of action. 47 In addition, we used autophagy-defective Becn1 +/− mice as well as Cftr F508del/F508del mice in a background of BECN1 haploinsufficiency ( Cftr F508del/F508del / Becn1 +/− mice). First, we analyzed the early steps following acute infection.…”

Section: Discussionmentioning

confidence: 99%

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation

Ferrari¹,

Monzani²,

Villella³

et al. 2017

Cell Death Dis

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Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

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Section: Discussionmentioning

confidence: 99%

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation

Ferrari¹,

Monzani²,

Villella³

et al. 2017

Cell Death Dis

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“…Additionally, six animal models expressing a variety of CFTR variants are now available (e.g. zebrafish, mouse, rat, rabbit, ferret, pig), although each has limitations regarding ease of use or degree to which human disease is recapitulated [35,36]. Finally, yeast phenomic screening has emerged as a means for discovery of gene-gene interaction networks and other features of CFTR class II and III variants [37,38,39], including identification and targeting of novel CFTR modulators in patient-derived epithelia [40].…”

Section: Recent Advances In Model Systemsmentioning

confidence: 99%

Transformative therapies for rare CFTR missense alleles

Oliver

Han

Sorscher

et al. 2017

Current Opinion in Pharmacology

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With over 1,900 variants reported in the cystic fibrosis transmembrane conductance regulator (CFTR), enhanced understanding of cystic fibrosis (CF) genotype-phenotype correlation represents an important and expanding area of research. The potentiator Ivacaftor has proven an effective treatment for a subset of individuals carrying missense variants, particularly those that impact CFTR gating. Therapeutic efforts have recently focused on correcting the basic defect resulting from the common F508del variant, as well as many less frequent missense alleles. Modest enhancement of F508del-CFTR function has been achieved by combining Ivacaftor with Lumacaftor, a compound that aids maturational processing of misfolded CFTR. Continued development of in silico and in vitro models will facilitate CFTR variant characterization and drug testing, thereby elucidating heterogeneity in the molecular pathogenesis, phenotype, and modulator responsiveness of CF.

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“…To begin with, the fact that CFTR knockout animal models do not recapitulate neutrophilic lung inflammation as seen in CF patients itself suggests that neutrophil dysfunction in CF patients is due to one or several coinciding mechanism(s) unique to humans, besides CFTR deficiency [90]. Additional support for this idea comes from a xenograft model in which human fetal tracheal tissues were implanted in severe combined immunodeficient mice [91].…”

Section: Reviewmentioning

confidence: 99%

Neutrophil plasticity enables the development of pathological microenvironments: implications for cystic fibrosis airway disease

Margaroli

Tirouvanziam

2016

Mol Cell Pediatr

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IntroductionThe pathological course of several chronic inflammatory diseases, including cystic fibrosis, chronic obstructive pulmonary disease, and rheumatoid arthritis, features an aberrant innate immune response dominated by neutrophils. In cystic fibrosis, neutrophil burden and activity of neutrophil elastase in the extracellular fluid have been identified as strong predictors of lung disease severity.ReviewAlthough neutrophils are generally considered to be rigid, pre-programmed effector leukocytes, recent studies suggest extensive plasticity in how neutrophil functions unfold upon recruitment to peripheral tissues, and how they choose their ultimate fate. Indeed, upon migration to cystic fibrosis airways, neutrophils display dysregulated lifespan, metabolic activation, and altered effector and regulatory functions, consistent with profound adaptation and phenotypic reprogramming. Licensed by signals present in cystic fibrosis airway microenvironment to survive and develop these novel functions, neutrophils orchestrate, in partnership with the epithelium and with the resident microbiota, the evolution of a pathological microenvironment. This microenvironment is defined by altered proteolytic, redox, and metabolic balance and the presence of stable luminal structures in which neutrophils and microbes coexist.ConclusionsThe elucidation of molecular mechanisms driving neutrophil plasticity in vivo will open new treatment opportunities designed to modulate, rather than block, the crucial adaptive functions fulfilled by neutrophils. This review aims to outline emerging mechanisms of neutrophil plasticity and their participation in the building of pathological microenvironments in the context of cystic fibrosis and other diseases with similar features.

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Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

Cited by 93 publications

References 117 publications

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation

Transformative therapies for rare CFTR missense alleles

Neutrophil plasticity enables the development of pathological microenvironments: implications for cystic fibrosis airway disease

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