title: Chronic airway infection/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia.
abstract: Hyperinflammatory responses to infection have been postulated as a component of cystic fibrosis (CF) lung disease. Studies have linked intracellular calcium (Ca(2+)(i)) mobilization with inflammatory responses in several systems. We have reported that the pro-inflammatory mediator bradykinin (BK) promotes larger Ca(2+)(i) signals in CF compared with normal bronchial epithelia, a response that reflects endoplasmic reticulum (ER)/Ca(2+) store expansion induced by chronic luminal airway infection/inflammation. The present study investigated whether CF airway epithelia were hyperinflammatory and, if so, whether the hyperinflammatory CF phenotype was linked to larger Ca(2+) stores in the ER. We found that DeltaF508 CF bronchial epithelia were hyperinflammatory as defined by an increased basal and mucosal BK-induced interleukin (IL)-8 secretion. However, the CF hyperinflammation expressed in short-term (6-11-day-old) primary cultures of DeltaF508 bronchial epithelia was lost in long-term (30-40-day-old) primary cultures of DeltaF508 bronchial epithelia, indicating this response was independent of mutant cystic fibrosis transmembrane conductance regulator. Exposure of 30-40-day-old cultures of normal airway epithelia to supernatant from mucopurulent material (SMM) from CF airways reproduced the increased basal and mucosal BK-stimulated IL-8 secretion of short-term CF cultures. The BK-triggered increased IL-8 secretion in SMM-treated cultures was mediated by an increased Ca(2+)(i) mobilization consequent to an ER expansion associated with increases in protein synthesis (total, cytokines, and antimicrobial factors). The increased ER-dependent, Ca(2+)(i)-mediated hyperinflammatory epithelial response may represent a general beneficial airway epithelial adaptation to transient luminal infection. However, in CF airways, the Ca(2+)(i)-mediated hyperinflammation may be ineffective in promoting the eradication of infection in thickened mucus and, consequently, may have adverse effects in the lung.
authors.affiliation: Cystic Fibrosis Center and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA. carla_ribeiro@med.unc.edu
authors.forename: Carla M Pedrosa
authors.initials: CM
authors.lastname: Ribeiro
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Paradiso
authors.forename: Ute
authors.initials: U
authors.lastname: Schwab
authors.forename: Juan
authors.initials: J
authors.lastname: Perez-Vilar
authors.forename: Lisa
authors.initials: L
authors.lastname: Jones
authors.forename: Wanda
authors.initials: W
authors.lastname: O'neal
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
mesh_terms: D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology*
chemical_list: D016209:Interleukin-8; D002118:Calcium