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J. Biol. Chem., Vol. 280, Issue 18, 17798-17806, May 6, 2005

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Chronic Airway Infection/Inflammation Induces a Ca²⁺_i-dependent Hyperinflammatory Response in Human Cystic Fibrosis Airway Epithelia^*

Carla M. Pedrosa Ribeiro, Anthony M. Paradiso, Ute Schwab, Juan Perez-Vilar, Lisa Jones, Wanda O'Neal, and Richard C. Boucher

From the Cystic Fibrosis Center and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

Hyperinflammatory responses to infection have been postulated as a component of cystic fibrosis (CF) lung disease. Studies have linked intracellular calcium (Ca²⁺_i) mobilization with inflammatory responses in several systems. We have reported that the pro-inflammatory mediator bradykinin (BK) promotes larger Ca²⁺_i signals in CF compared with normal bronchial epithelia, a response that reflects endoplasmic reticulum (ER)/Ca²⁺ 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 Ca²⁺ stores in the ER. We found that F508 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 F508 bronchial epithelia was lost in long-term (30–40-day-old) primary cultures of F508 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 Ca²⁺_i mobilization consequent to an ER expansion associated with increases in protein synthesis (total, cytokines, and antimicrobial factors). The increased ER-dependent, Ca²⁺_i-mediated hyperinflammatory epithelial response may represent a general beneficial airway epithelial adaptation to transient luminal infection. However, in CF airways, the Ca²⁺_i-mediated hyperinflammation may be ineffective in promoting the eradication of infection in thickened mucus and, consequently, may have adverse effects in the lung.

Received for publication, September 15, 2004 , and in revised form, March 2, 2005.

^* This work was supported by Grants RIBEIR00Z0 and RIBEIR00G0 from The Cystic Fibrosis Foundation (to C. M. P. R.), National Institutes of Health Grants HL34322 and HL60280 (to R. C. B.), and Grant P30 DK34987 to University of North Carolina Immunotechnologies Core for cytokine assays. The authors have declared that no conflict of interest existed. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Microbiology and Immunology, C5111 Veterinary Medical Center, Cornell University College of Veterinary Medicine, Ithaca, NY 14853.

To whom correspondence should be addressed: Cystic Fibrosis Center and Dept. of Medicine, University of North Carolina, CB #7248, 7013 Thurston-Bowles Bldg., Chapel Hill, NC 27599-7248. Tel.: 919-966-7045; Fax: 919-966-5178; E-mail: carla_ribeiro{at}med.unc.edu.

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