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Drugs in R&D
Published in: Drugs in R&D 1/2006

01-01-2006 | Review Article

The Role of Intracellular Calcium Signals in Inflammatory Responses of Polarised Cystic Fibrosis Human Airway Epithelia

Author: Dr Carla Maria Pedrosa Ribeiro

Published in: Drugs in R&D | Issue 1/2006

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Abstract

Hyperinflammatory host responses to bacterial infection have been postulated to be a key step in the pathogenesis of cystic fibrosis (CF) lung disease. Previous studies have indicated that the CF airway epithelium itself contributes to the hyperinflammation of CF airways via an excessive inflammatory response to bacterial infection. However, it has been controversial whether the hyperinflammation of CF epithelia results from mutations in the CF transmembrane conductance regulator (CFTR) and/or is a consequence of persistent airways infection.
Recent studies have demonstrated that intracellular calcium (Ca2+ i) signals consequent to activation of apical G protein-coupled receptors (GPCRs) by pro-inflammatory mediators are increased in CF airway epithelia. Because of the relationship between Ca2+ i mobilisation and inflammatory responses, the mechanism for the increased Ca2+ i signals in CF was investigated and found to result from endoplasmic reticulum (ER) Ca2+ store expansion. The ER Ca2+ store expansion imparts a hyperinflammatory phenotype to chronically infected airway epithelia as a result of the larger Ca2+ i mobilisation coupled to an excessive inflammatory response following GPCR activation.
The ER expansion is not dependent on ER retention of misfolded ΔF508 CFTR, but reflects an epithelial response acquired following persistent luminal airway infection. With respect to the mechanism of ER expansion in CF, the current view is that chronic airway epithelial infection triggers an unfolded protein response as a result of the increased flux of newly synthesised inflammatory mediators and defensive factors into the ER compartment. This unfolded protein response is coupled to X-box binding protein 1 (XBP-1) mRNA splicing and transcription of genes associated with the expansion of the protein-folding capacity of the ER (e.g. increases in ER chaperones and ER membranes).
These studies have revealed a novel adaptive response in chronically infected airway epithelia, where the increased protein secretory capacity serves to promote epithelial homeostasis by increasing both the secretory and the reparative capacity of the cell. In addition, the increased ER-derived Ca2+ i signaling allows the epithelia to amplify its inflammatory responses to infectious agents and exogenous toxicants.
This review is devoted to a discussion of these recent findings and their implication for Ca2+ i-dependent hyperinflammatory responses in CF airways.
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Metadata
Title
The Role of Intracellular Calcium Signals in Inflammatory Responses of Polarised Cystic Fibrosis Human Airway Epithelia
Author
Dr Carla Maria Pedrosa Ribeiro
Publication date
01-01-2006
Publisher
Springer International Publishing
Published in
Drugs in R&D / Issue 1/2006
Print ISSN: 1174-5886
Electronic ISSN: 1179-6901
DOI
https://doi.org/10.2165/00126839-200607010-00002

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