Ribeiro Carla Maria Pedrosa
Cystic Fibrosis/Pulmonary Research and Treatment Center and the Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 25799, USA.
Drugs R D. 2006;7(1):17-31. doi: 10.2165/00126839-200607010-00002.
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 DeltaF508 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.
超炎症性宿主对细菌感染的反应被认为是囊性纤维化（CF）肺部疾病发病机制中的关键步骤。先前的研究表明，CF气道上皮本身通过对细菌感染的过度炎症反应导致CF气道的超炎症状态。然而，CF上皮细胞的超炎症是由CF跨膜传导调节因子（CFTR）突变引起的和/或是否是持续性气道感染的结果一直存在争议。最近的研究表明，促炎介质激活顶端G蛋白偶联受体（GPCR）后，CF气道上皮细胞内的细胞内钙（Ca2+i）信号增加。由于Ca2+i动员与炎症反应之间的关系，对CF中Ca2+i信号增加的机制进行了研究，发现是内质网（ER）Ca2+储存扩张所致。由于GPCR激活后较大的Ca2+i动员与过度的炎症反应相结合，ER Ca2+储存扩张赋予慢性感染的气道上皮超炎症表型。ER扩张不依赖于错误折叠的DeltaF508 CFTR在内质网的滞留，而是反映了持续性管腔气道感染后获得的上皮反应。关于CF中ER扩张的机制，目前的观点是，慢性气道上皮感染由于新合成的炎症介质和防御因子进入ER区室的通量增加而触发未折叠蛋白反应。这种未折叠蛋白反应与X盒结合蛋白1（XBP-1）mRNA剪接以及与ER蛋白折叠能力扩张相关的基因转录（例如ER伴侣蛋白和ER膜的增加）相关联。这些研究揭示了慢性感染气道上皮中的一种新型适应性反应，其中增加的蛋白质分泌能力通过增加细胞的分泌和修复能力来促进上皮稳态。此外，增加的ER衍生的Ca2+i信号传导使上皮细胞能够放大其对感染因子和外源性毒物的炎症反应。本综述致力于讨论这些最新发现及其对CF气道中Ca2+i依赖性超炎症反应的影响。
