Key points are not available for this paper at this time.
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 ΔF508 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 ΔF508 bronchial epithelia was lost in long-term (30–40-day-old) primary cultures of ΔF508 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. 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 ΔF508 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 ΔF508 bronchial epithelia was lost in long-term (30–40-day-old) primary cultures of ΔF508 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. In CF 1The abbreviations used are: CF, cystic fibrosis; Ca2+i, intracellular calcium; BK, bradykinin; ER, endoplasmic reticulum; SMM, supernatant from mucopurulent material; CFTR, cystic fibrosis transmembrane conductance regulator; NF, nuclear factor; GPCR, G protein-coupled receptor; IL, interleukin; BIP, immunoglobulin-binding protein; PDI, protein disulfide isomerase; XBP-1, X-box binding protein-1; TG, thapsigargin; IRE1, inositol requiring 1; ATF6, activating transcription factor 6; PBS, phosphate-buffered saline; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid. airway epithelia, the absence of the cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl– secretion, coupled with increased Na+ absorption, results in a reduced periciliary liquid layer depth (1Matsui H. Grubb B.R. Tarran R. Randell S.H. Gatzy J.T. Davis C.W. Boucher R.C. Cell. 1998; 95: 1005-1015Abstract Full Text Full Text PDF PubMed Scopus (936) Google Scholar), adherence of thickened mucus to airway surfaces, and persistent airway infections (2Konstan M.W. Hilliard K.A. Norvell T.M. Berger M. Am. J. Respir. Crit. Care Med. 1994; 150: 448-454Crossref PubMed Scopus (475) Google Scholar, 3Khan T.Z. Wagener J.S. Bost T. Martinez J. Accurso F.J. Riches D.W.H. Am. J. Respir. Crit. Care Med. 1995; 151: 1075-1082PubMed Google Scholar, 4Muhlebach M.S. Stewart P.W. Leigh M.W. Noah T.L. Am. J. Respir. Crit. Care Med. 1999; 160: 186-191Crossref PubMed Scopus (310) Google Scholar, 5Leigh M.W. Disorders of the Respiratory Tract of Children. W. B. Saunders, Philadelphia1998Google Scholar). It remains controversial whether the inflammatory response of CF airways to infection is intrinsically excessive and, thus, accelerates lung disease. As evidence for excessive inflammation, cytokines are elevated in sputa from CF compared with disease control (asthmatic) patients (6Koller D.Y. Nething I. Otto J. Urbanek R. Eichler I. Am. J. Respir. Crit. Care Med. 1997; 155: 1050-1054Crossref PubMed Scopus (73) Google Scholar), and bronchoalveolar lavage studies have revealed higher levels of cytokines and inflammatory cells referenced to bacterial number or endotoxin levels in CF versus non-CF patients with acute lung infection (4Muhlebach M.S. Stewart P.W. Leigh M.W. Noah T.L. Am. J. Respir. Crit. Care Med. 1999; 160: 186-191Crossref PubMed Scopus (310) Google Scholar, 7Muhlebach M.S. Noah T.L. Am. J. Respir. Crit. Care Med. 2002; 165: 911-915Crossref PubMed Scopus (112) Google Scholar). Many studies have addressed the magnitude of airway epithelial inflammatory responses to infection in CF by focusing on the regulation of cytokine production by the transcription factor nuclear factor (NF)-κB (8Konstan M.W. Berger M. Pediatr. Pulmonol. 1997; 24: 137-142Crossref PubMed Scopus (2) Google Scholar, 9Bals R. Weiner D.J. Wilson J.M. J. Clin. Investig. 1999; 103: 303-307Crossref PubMed Scopus (166) Google Scholar), including its regulation by toll receptors (10Akira S. Takeda K. Kaisho T. Nat. Immunol. 2001; 2: 675-680Crossref PubMed Scopus (3958) Google Scholar). In addition, intracellular calcium (Ca2+i) signals resulting from heterotrimeric G protein-coupled receptor (GPCR) activation by inflammatory mediators or infectious agents also modulate NF-κB activation by a Ca2+i-dependent mechanism (11Hu Q. Deshpande S. Irani K. Ziegelstein R.C. J. Biol. Chem. 1999; 274: 33995-33998Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 12Quinlan K.L. Naik S.M. Cannon G. Armstrong C.A. Bunnett N.W. Ansel J.C. Caughman S.W. J. Immunol. 1999; 163: 5656-5665PubMed Google Scholar, 13Han B. Logsdon C.D. Am. J. Physiol. 2000; 278: C344-C351Crossref PubMed Google Scholar, 14Ouellet M. Barbeau B. Tremblay M.J. J. Biol. Chem. 1999; 274: 35029-35036Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 15Gewirtz A.T. Rao A.S. Simon Jr., P.O. Merlin D. Carnes D. Madara J.L. Neish A.S. J. Clin. Investig. 2000; 105: 79-92Crossref PubMed Scopus (175) Google Scholar, 16Jefferson K.K. Smith Jr., J. Immunol. 1999; 163: Google Scholar, M.S. S. M.S. 1999; PubMed Scopus Google Scholar). the pro-inflammatory mediator bradykinin (BK) Ca2+i mobilization Boucher R.C. Am. J. Physiol. Google and interleukin (IL)-8 secretion in non-CF and CF airway epithelia S. Am. J. Physiol. 2002; Scholar). the CF and IL-8 secretion by a Ca2+i mechanism in airway epithelial cells R. S. D. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We have that or receptor activation larger Ca2+i signals in CF compared with normal airway epithelia Boucher R.C. J. Physiol. 2001; PubMed Scopus Google Scholar, Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and this Ca2+i response results from luminal of the endoplasmic reticulum Ca2+ stores Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The that the Ca2+i responses a to the of CF hyperinflammation was by studies of in a for cells expressed a ER Ca2+ consequent to an increased ER linked to the of this disease D. G. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). in disease have been associated with increases in ER Ca2+ and cytokine production Q. K. J. 1997; PubMed Google Scholar, 1995; PubMed Scopus Google Scholar). In the of CF, the ER cytokine and CF airways are In the present the that CF airway epithelia a hyperinflammatory phenotype resulting from luminal of ER investigated the whether CF airway epithelia have increased IL-8 in response to the inflammatory as compared with normal airway whether this response is an epithelial adaptation to luminal or on mutant ΔF508 and whether Ca2+i responses to the increased cytokine in an in for CF airway epithelial and and cells were the of by the on the of the of from and were the of lung from or were in and in or used for epithelial cells were by the of and CF cells were and as Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were an and primary cultures were or IL-8 or from CF airways with from CF IL-8 secretion, the were from short-term or long-term cultures of normal and CF bronchial IL-8 was by in Studies with from CF material was from the airway of CF with and S. the of and by the of the of as Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). material was and the supernatant was a and studies revealed that of airway epithelia with from CF with and S. induced epithelial of the of and the number of from CF and ΔF508 and were to or was to the mucosal of normal or CF bronchial epithelia, and the were to the inflammatory response of normal versus CF cultures to luminal cultures were with or SMM, and a was for IL-8 secretion. to whether SMM-treated cultures were to a inflammatory cultures were with or for and the were by by mucosal or and of IL-8 secretion. to the of Ca2+i mobilization on BK-induced IL-8 secretion, cultures were with or for by of the and as Boucher R.C. J. Physiol. 2001; PubMed Scopus Google Scholar). was to cultures in a Boucher R.C. J. Physiol. 2001; PubMed Scopus Google Scholar), and Ca2+i mobilization was as reported Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google in IL-8 the was to the of on and secretion, cultures were with or for to and the were and for cytokine to the of on protein the of by cultures with PubMed Scopus Google was of or of ER of ER in cultures of bronchial airway epithelia or bronchial epithelial was to a of J. Jr., J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). or epithelial were with the primary a and a for and PDI, by a and a As the primary were The signals were by in the or The of the of and was to a Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were from and of were in the with the The and for were to the from normal bronchial epithelial cultures in or normal versus CF bronchial epithelia in on the The from the of were from cultures and bronchial epithelial of was an adaptation of a H. T. T. K. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. D. 2002; PubMed Scopus Google Scholar). bronchial epithelial cultures were with of or for or for by with of was to the mucosal and surfaces, and cultures were was and of was by of were to a of number The a by IRE1, results in a that for an transcription The a is The was for of for for and for by of for and The were on a a and with to the and the the of a was the from and SMM-treated cultures. was on a to the and with the from were with a of was used to in from and SMM-treated cultures the was to and the was from the and were for by and by in the was a control to or SMM-treated were in and were the As a control was also in on of the of were as reported M.W. 2001; Scopus Google Scholar). represent the from from and were by or of was defined as of CF and BK-stimulated IL-8 whether CF airway epithelia compared the basal IL-8 secretion in normal versus ΔF508 CF primary bronchial epithelial cultures. that the IL-8 secretion was increased in short-term CF compared with normal cultures. The of the pro-inflammatory on IL-8 secretion was in primary cultures of normal and ΔF508 CF bronchial with a of Boucher R.C. Am. J. Physiol. Google IL-8 secretion in CF compared with normal cultures that short-term primary cultures of CF bronchial airway epithelia a hyperinflammatory the CF Hyperinflammatory the of an ΔF508 or an to this IL-8 secretion basal and BK-stimulated was in long-term normal versus ΔF508 CF primary bronchial epithelial cultures. that the increased IL-8 secretion in short-term CF cultures compared with normal cultures was lost in 30–40-day-old CF cultures in the to mucosal IL-8 secretion as 30–40-day-old normal cultures that the hyperinflammatory in short-term CF cultures represent a to the ΔF508 is a response to the persistent found in CF airways in that with in the absence of the the CF Hyperinflammatory to by Exposure to CF for the of persistent infection and on hyperinflammatory a from CF airway the of airway epithelial cultures to for and basal and BK-induced IL-8 IL-8 secretion was investigated in long-term 30–40-day-old primary cultures of normal and CF bronchial epithelia to mucosal for to that the acute IL-8 secretion, this response was in long-term normal and CF cultures for We whether a hyperinflammatory an increased IL-8 response to mucosal BK, in normal airway epithelia and whether this response was in long-term cultures of CF 30–40-day-old normal epithelia an increased IL-8 secretion to compared with 30–40-day-old normal epithelia to in the absence of an increased IL-8 secretion was induced in 30–40-day-old CF cultures for with as compared with cultures the IL-8 response of CF cultures in the absence or of mucosal was to that of normal cultures. an hyperinflammatory associated with the ΔF508 that chronic (SMM) the hyperinflammatory the Hyperinflammatory the IL-8 in with the of to Ca2+i receptors are coupled to Ca2+i mobilization Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). investigated whether activation of this of receptors with IL-8 secretion in airway epithelia and, if so, whether this a mucosal induced a in IL-8 secretion in 30–40-day-old normal bronchial epithelia compared with cultures In cultures with higher levels of IL-8 in response to mucosal compared with cultures that the increased IL-8 secretion by activation of receptors in cultures may be a general associated with the activation of that increased Ca2+i mobilization in airway epithelia Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). IL-8 on of the ER Ca2+ the of Ca2+i signals on the inflammatory investigated BK-induced Ca2+i mobilization in 30–40-day-old normal bronchial airway epithelial cultures with versus for Ca2+i mobilization in and SMM-treated the Ca2+i was in SMM-treated epithelia and The for an of ER Ca2+ store in airway Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that increased the ER Ca2+ stores that be receptor activation a to Ca2+i signals in airway epithelia Boucher R.C. J. Physiol. 2001; PubMed Scopus Google Scholar), the of was in or cultures and We the of Ca2+i on IL-8 secretion in epithelia with versus for that was ineffective in IL-8 secretion in cultures. In the component of IL-8 secretion in SMM-treated cultures was by that IL-8 secretion by and We that the absence of an of Ca2+i on BK-induced IL-8 responses in cultures reflects the that the BK-induced Ca2+i signals in cells with normal ER Ca2+ stores the to the Ca2+i-mediated component of IL-8 secretion In the larger Ca2+i signals resulting from the of ER Ca2+ stores by were to a Ca2+i-dependent activation of in IL-8 secretion. the component of BK-induced IL-8 secretion in normal airway epithelia, cultures were for with the ER to the ER Ca2+ stores Jr., J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). As in the IL-8 response to in cultures ER Ca2+ stores were with was the as that in cultures. on IL-8 secretion in cultures that receptor activation a component of IL-8 secretion in and cultures as and a component that of ER Ca2+ stores and to ER and Ca2+ have that mucosal of 30–40-day-old primary cultures of normal bronchial epithelia with from CF airways expansion of the ER and increases its Ca2+ stores Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ER expansion be by that protein or infection S.W. J. Immunol. 2001; PubMed Scopus Google Scholar, J. 2002; PubMed Scopus Google Scholar, J. H. J. J. 2002; PubMed Scopus (26) Google Scholar, K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 2001; PubMed Scopus Google Scholar, A.S. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. K. S.M. Cell. Biol. 2002; Scholar, S. M. J. Biol. PubMed Scopus Google Scholar). whether an in protein synthesis by cytokine and protein synthesis in the absence and of induced IL-8 secretion that was for compared with cultures As a of long-term normal cultures with supernatant from luminal material from the of normal an IL-8 secretion that was higher that by SMM-treated long-term normal cultures also increased secretion of and compared with cultures and the levels of the antimicrobial were increased by in SMM-treated cultures compared with cultures The increased secretion of cytokines was a component of a larger in protein of 30–40-day-old normal airway epithelia with for increased protein synthesis by compared with cultures that cytokine secretion and antimicrobial are of a general in protein synthesis associated with expansion of the ER and ER Ca2+ stores Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of with of ER in in protein are in the ER by that the of that the of normal K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 2001; PubMed Scopus Google Scholar, A.S. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. K. S.M. Cell. Biol. 2002; Scholar). In increased protein synthesis is by ER W. 1998; PubMed Scopus Google Scholar, M. D. J. 1998; PubMed Scopus Google and the activating transcription factor K. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. K. S.M. Cell. Biol. 2002; Scholar, D. 1999; PubMed Scopus Google Scholar). with increased protein the ER a D. Nat. Biol. 2000; 2: PubMed Scopus Google Scholar, H. M. K. Biol. Cell. PubMed Scopus Google to the of the and its Biol. 2001; PubMed Scopus Google Scholar, D. M. K. S.M. Cell. Biol. 2002; Scholar). the transcription factor of a and a of the H. T. T. K. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. D. 2002; PubMed Scopus Google Scholar). The resulting is a transcription factor that as ER in protein and A.S. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. 2000; PubMed Google Scholar). ATF6, on the activation to a transcription factor that is for transcription of ER as as H. K. H. T. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). We whether increases in protein synthesis induced by of 30–40-day-old normal bronchial epithelia the of mucosal versus on in cultures. induced an of or also induced increases of as compared with cultures was increased that regulation of was by infection/inflammation. In addition, of 30–40-day-old normal bronchial epithelia with increased and protein and results that of is associated with increases in the of the ER whether persistent luminal was also associated with of increased ER protein synthesis in CF airway epithelia, the of the ER and in CF bronchial epithelia from The of that of the ER in airway epithelia as reported Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and was increased in CF compared with normal epithelia G and that chronic airway increases in protein synthesis an ER response associated with ER expansion and an increased ER protein in CF epithelia in of the ER expansion was an in and protein levels in the ER Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that increased ER Ca2+ resulting in the Ca2+i signals in response to activation that IL-8 The of CF airway disease is infection to the to thickened mucus from the CF lung D. Tarran R. M. G. Berger J. T. K. Randell S. Boucher R.C. G. J. Clin. Investig. 2002; PubMed Scopus Google Scholar). epithelia an in the response to the bacterial infection of mucus by an of inflammatory mediators and antimicrobial the airway J. Med. 1995; Google Scholar, D. J. Clin. Immunol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, G. D. Immunol. 2000; PubMed Scopus Google Scholar). The the magnitude of the inflammatory to airway and, in that infection in CF airways K. R. Med. J. 1995; PubMed Scopus Google Scholar, K. R. J. Am. J. Respir. Crit. Care Med. 1997; PubMed Scopus Google Scholar). However, the and responses to a defined bacterial may be in CF in normal airways, are (4Muhlebach M.S. Stewart P.W. Leigh M.W. Noah T.L. Am. J. Respir. Crit. Care Med. 1999; 160: 186-191Crossref PubMed Scopus (310) Google Scholar, 7Muhlebach M.S. Noah T.L. Am. J. Respir. Crit. Care Med. 2002; 165: 911-915Crossref PubMed Scopus (112) Google Scholar, M. Am. J. Respir. Crit. Care Med. 2002; 165: PubMed Scopus Google Scholar). that the magnitude of the cytokine secretion to airways infection is Ca2+i, and the responses and cytokine secretion to activation of transcription as have the activation of NF-κB activation and Ca2+i-dependent secretion of inflammatory mediators (11Hu Q. Deshpande S. Irani K. Ziegelstein R.C. J. Biol. Chem. 1999; 274: 33995-33998Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 12Quinlan K.L. Naik S.M. Cannon G. Armstrong C.A. Bunnett N.W. Ansel J.C. Caughman S.W. J. Immunol. 1999; 163: 5656-5665PubMed Google Scholar, 13Han B. Logsdon C.D. Am. J. Physiol. 2000; 278: C344-C351Crossref PubMed Google Scholar, 14Ouellet M. Barbeau B. Tremblay M.J. J. Biol. Chem. 1999; 274: 35029-35036Abstract Full Text Full Text PDF PubMed Scopus (26) Google and infectious or Ca2+i A.T. Rao A.S. Simon Jr., P.O. Merlin D. Carnes D. Madara J.L. Neish A.S. J. Clin. Investig. 2000; 105: 79-92Crossref PubMed Scopus (175) Google Scholar, 16Jefferson K.K. Smith Jr., J. Immunol. 1999; 163: Google Scholar, M.S. S. M.S. 1999; PubMed Scopus Google Scholar). the that in airway epithelial Ca2+i be in the excessive inflammatory responses of CF have revealed that CF airway epithelia larger responses normal epithelia or receptor an expansion of the ER Ca2+ stores Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the present the that CF airway epithelia excessive inflammatory as by IL-8 secretion, to increased responses resulting from store that primary cultures of CF airway epithelia are hyperinflammatory as short-term cultures However, the CF hyperinflammatory phenotype is to chronic luminal and is independent of ΔF508 on the long-term primary cultures of CF airway epithelia increased or IL-8 secretion in the absence of luminal infection for the IL-8 responses of long-term primary CF and normal airway epithelial cultures to were and a hyperinflammatory the IL-8 secretion, be induced in long-term normal airway epithelia by luminal to and been controversial whether the ΔF508 is linked with a hyperinflammatory CF airway epithelial response Randell S.H. Pediatr. Pulmonol. Scholar), that the hyperinflammatory of CF airway epithelia an epithelial response to the chronic found in CF airway in and is independent of mutant study revealed that a mechanism of CF airway epithelial hyperinflammation reflects an in ER Ca2+i on the the hyperinflammatory in short-term primary cultures of CF epithelia was associated with larger Ca2+i mobilization normal cultures Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of normal cultures to mucosal Ca2+i as a of ER Ca2+ store expansion the larger mucosal Ca2+i signals from short-term primary cultures of CF bronchial epithelia Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the hyperinflammation increased mucosal IL-8 secretion resulting from was by Ca2+i with and that the larger magnitude of resulting from receptor activation in SMM-treated cultures the for Ca2+i-dependent activation of IL-8 The the and of IL-8 protein secretion reflects the of activation of Ca2+i-dependent transcription PubMed Google and protein on that BK-induced NF-κB is from and to the for of resulting in persistent activation PubMed Google Scholar), the of Ca2+i levels levels Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of Ca2+i responses in CF in the present study is in with of increases in ER Ca2+ stores in the of disease D. G. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google and disease Q. K. J. 1997; PubMed Google Scholar, 1995; PubMed Scopus Google Scholar), may in the of ER expansion in In the of CF, that an airway epithelial adaptation to chronic luminal by is the increased synthesis and secretion of cytokines and antimicrobial The increased protein synthesis an increased ER protein an ER response that is by increased and increased of ER and expansion of the ER and its Ca2+ stores Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for the increased protein synthesis and ER expansion been the and The of secretion by cells ER expansion S. M. J. Biol. PubMed Scopus Google Scholar), and this on J. D. M.J. 2001; PubMed Scopus Google Scholar). The chronic airway epithelial ER and an in ER Ca2+ stores was reported in studies that increases in the ER and the ER Ca2+ store Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ER expansion been in response to of bacterial infection D.J. 1998; PubMed Scopus Google Scholar). ER expansion on the adaptation by airway epithelia to infection in a adaptation to the increased protein synthesis for increases in secretion of and may the inflammatory response to persistent airway infection. airway epithelia to bacterial infection for ER Ca2+ stores to higher levels of cytokines as a of increased Ca2+i mobilization in response to that as and Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We that normal the of the inflammatory response consequent to expansion of stores is the increased inflammatory IL-8 secretion that may of infection in of inflammatory cells to the of infection and In CF, cytokine responses chronic bacterial infection may be the are in the thickened mucus in CF airways, and inflammatory cells D. Tarran R. M. G. Berger J. T. K. Randell S. Boucher R.C. G. J. Clin. Investig. 2002; PubMed Scopus Google Scholar). the persistent ineffective inflammatory in CF may have an adverse on the of the airway the bacterial of the of that to the CF hyperinflammatory phenotype is in The is persistent airway infection response to this the increased epithelial synthesis and secretion of antimicrobial and cytokines ER expansion and increased ER Ca2+ stores The consequent in the magnitude of Ca2+i signals a component of CF airway the epithelial cells to cytokines a Ca2+i-dependent in response to luminal In CF, of this response are Boucher R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), may be the increased Ca2+i-dependent IL-8 secretion inflammatory cells that are ineffective in mucus and airway by the to the to airway is to the persistent mucus from CF airway We Randell for and primary and for and primary cells and for
Ribeiro et al. (Fri,) studied this question.