Is Cystic Fibrosis Lung Disease Caused by Abnormal Ion Composition or Abnormal Volume?

Krouse, Mauri E.

doi:10.1085/jgp.118.2.219

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…Consequently, the loss of ENaC inhibition leads to increased sodium influx, resulting in airway surface liquid (ASL) dehydration and decreased periciliary volume, generating in turn cilia compression and affecting muco-ciliary clearance. In addition, the defective CFTR prevents chloride to follow sodium influx, inducing chloride to be retained in the ASL ( Krouse, 2001 ), as the more recently identified alternative chloride channels TMEM16A and SLC26A9 do not appear to counterbalance impaired anion transport in CF patients ( Mall and Galietta, 2015 ; Martin et al, 2018 ). In addition, decreased bicarbonate secretion associated to an increased H + secretion by ATP12A (an H + /K + ATPase channel) in CF patients induces mucus acidification, preventing efficient mucin expansion and generating defective mucus with altered adherence properties ( Ratjen et al, 2015 ).…”

Section: Epithelial Alterations In Chronic Respiratory Diseasesmentioning

confidence: 99%

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

2021

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Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches.

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Section: Epithelial Alterations In Chronic Respiratory Diseasesmentioning

confidence: 99%

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

2021

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“…13,14 The resolution of this controversy (abnormal ion composition or abnormal water volume) is key to understanding the lung pathophysiology and to treat the initial events of CF disease. 15,16 How defective CFTR function affects the regulation of NF-B-dependent genes remains to be determined. New evidence supports the idea that defective CFTR causes a dysregulation of cytokine expression both in airway epithelial cells and blood peripheral T cells of CF patients.…”

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confidence: 99%

Interleukin-10 Inhibits Elevated Chemokine Interleukin-8 and Regulated on Activation Normal T Cell Expressed and Secreted Production in Cystic Fibrosis Bronchial Epithelial Cells by Targeting the IkB Kinase α/β Complex

Tabary

Muselet

Escotte

et al. 2003

The American Journal of Pathology

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Accumulating evidence suggests that in cystic fibrosis (CF) patients, airway fluids are characterized by decreased antibacterial activity, elevated NaCl concentration, and high levels of chemokines, resulting in exaggerated activation of the transcriptional nuclear factor (NF)-kappaB in airway epithelial cells. The present study was undertaken to evaluate the effects of anti-inflammatory cytokine interleukin-10 (IL-10) on NaCl-induced chemokine IL-8 and regulated on activation normal T cell expressed and secreted (RANTES) expression through the NF-kappaB signaling in primary deltaF508 CF and non-CF (control) human bronchial epithelial cells. Exposure of CF and non-CF bronchial epithelial cells to hypertonic (170 mmol/L NaCl) milieu compared to isotonic (115 mmol/L NaCl) and hypotonic (85 mmol/L NaCl) milieu caused a significant, NaCl-dependent increase in IL-8 and RANTES gene expression and protein production. Compared to non-CF cells, CF bronchial epithelial cells were characterized by a higher susceptibility to produce elevated IL-8 and RANTES production in an hypertonic NaCl milieu in response to IL-1beta activation. Treatment with IL-10 suppressed IL-8 and RANTES gene expression in both non-CF and CF bronchial epithelial cells was associated with a reduced expression of I(k)B (IKK) alpha/beta kinases, particularly for IKKalpha which is greater expressed in CF bronchial epithelial cells, and resulting in reduced NF-kappaB activation. These findings suggest that IL-10 might have anti-inflammatory benefits in airways of CF patients.

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“…The loss of these receptors leads to deceased complement-dependent phagocytosis. Hypersalinity of the airway surface fluid has been shown to inhibit the killing actions of epithelial cells in the CF lung through inactivation of β-defensin-1 and potentially other antimicrobials, although these findings are considered somewhat controversial in the CF field (Smith et al, 1996 ; Goldman et al, 1997 ; Krouse, 2001 ). Peripheral PMNs isolated from CF patients show comparable NET formation to normal PMNs, but there is also evidence that PMNs in the CF lung environment display increased NET formation that contributes to the pulmonary obstruction typical in CF (Marcos et al, 2010 ; Young et al, 2011 ).…”

Section: Functions Of Normal Pmns and Defects In Cgd And Cf Patientsmentioning

confidence: 99%

Influence of Neutrophil Defects on Burkholderia cepacia Complex Pathogenesis

Porter¹,

Goldberg²

2011

Front. Cell. Inf. Microbio.

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The Burkholderia cepacia complex (Bcc) is a group of Gram-negative bacteria that are ubiquitous in the environment and have emerged as opportunistic pathogens in immunocompromised patients. The primary patient populations infected with Bcc include individuals with cystic fibrosis (CF), as well as those with chronic granulomatous disease (CGD). While Bcc infection in CF is better characterized than in CGD, these two genetic diseases are not obviously similar and it is currently unknown if there is any commonality in host immune defects that is responsible for the susceptibility to Bcc. CF is caused by mutations in the CF transmembrane conductance regulator, resulting in manifestations in various organ systems, however the major cause of morbidity and mortality is currently due to bacterial respiratory infections. CGD, on the other hand, is a genetic disorder that is caused by defects in phagocyte NADPH oxidase. Because of the defect in CGD, phagocytes in these patients are unable to produce reactive oxygen species, which results in increased susceptibility to bacterial and fungal infections. Despite this significant defect in microbial clearance, the spectrum of pathogens frequently implicated in infections in CGD is relatively narrow and includes some bacterial species that are considered almost pathognomonic for this disorder. Very little is known about the cause of the specific susceptibility to Bcc over other potential pathogens more prevalent in the environment, and a better understanding of specific mechanisms required for bacterial virulence has become a high priority. This review will summarize both the current knowledge and future directions related to Bcc virulence in immunocompromised individuals with a focus on the roles of bacterial factors and neutrophil defects in pathogenesis.

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Is Cystic Fibrosis Lung Disease Caused by Abnormal Ion Composition or Abnormal Volume?

Cited by 12 publications

References 28 publications

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

Interleukin-10 Inhibits Elevated Chemokine Interleukin-8 and Regulated on Activation Normal T Cell Expressed and Secreted Production in Cystic Fibrosis Bronchial Epithelial Cells by Targeting the IkB Kinase α/β Complex

Influence of Neutrophil Defects on Burkholderia cepacia Complex Pathogenesis

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