Dept. of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Sep 15;303(6):L509-18. doi: 10.1152/ajplung.00226.2011. Epub 2012 Jul 20.
In the clinical setting, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene enhance the inflammatory response in the lung to Pseudomonas aeruginosa (P. aeruginosa) infection. However, studies on human airway epithelial cells in vitro have produced conflicting results regarding the effect of mutations in CFTR on the inflammatory response to P. aeruginosa, and there are no comprehensive studies evaluating the effect of P. aeruginosa on the inflammatory response in airway epithelial cells with the ΔF508/ΔF508 genotype and their matched CF cell line rescued with wild-type (wt)-CFTR. CFBE41o- cells (ΔF508/ΔF508) and CFBE41o- cells complemented with wt-CFTR (CFBE-wt-CFTR) have been used extensively as an experimental model to study CF. Thus the goal of this study was to examine the effect of P. aeruginosa on gene expression and cytokine/chemokine production in this pair of cells. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2 and TNF-α) in CFBE-wt-CFTR cells compared with CFBE-ΔF508-CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt-CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o-ΔF508/ΔF508-CFTR cells. Taken together with other published studies, our data demonstrate that there is no compelling evidence to support the view that mutations in CFTR induce a hyperinflammatory response in human airway epithelial cells in vivo. Although the lungs of patients with CF have abundant levels of proinflammatory cytokines and chemokines, because the lung is populated by immune cells and epithelial cells there is no way to know, a priori, whether airway epithelial cells in the CF lung in vivo are hyperinflammatory in response to P. aeruginosa compared with non-CF lung epithelial cells. Thus studies on human airway epithelial cell lines and primary cells in vitro that propose to examine the effect of mutations in CFTR on the inflammatory response to P. aeruginosa have uncertain clinical significance with regard to CF.
在临床环境中，囊性纤维化跨膜电导调节因子 (CFTR) 基因突变增强了肺部对铜绿假单胞菌 (P. aeruginosa) 感染的炎症反应。然而，体外人呼吸道上皮细胞的研究对于 CFTR 基因突变对铜绿假单胞菌炎症反应的影响产生了相互矛盾的结果，并且没有全面的研究评估铜绿假单胞菌对具有 ΔF508/ΔF508 基因型的气道上皮细胞炎症反应的影响及其用野生型 (wt)-CFTR 挽救的匹配 CF 细胞系。CFBE41o-细胞 (ΔF508/ΔF508) 和用 wt-CFTR 互补的 CFBE41o-细胞 (CFBE-wt-CFTR) 已被广泛用作研究 CF 的实验模型。因此，本研究的目的是研究铜绿假单胞菌对这对细胞中基因表达和细胞因子/趋化因子产生的影响。与 CFBE-ΔF508-CFTR 细胞相比，铜绿假单胞菌在 CFBE-wt-CFTR 细胞中引起细胞因子和趋化因子表达（例如 IL-8、CXCL1、CXCL2 和 TNF-α）的更强烈增加。这些结果表明，用 wt-CFTR 互补的 CFBE41o-细胞对铜绿假单胞菌的炎症反应比 CFBE41o-ΔF508/ΔF508-CFTR 细胞更强烈。结合其他已发表的研究，我们的数据表明，没有令人信服的证据支持 CFTR 基因突变在体内诱导人呼吸道上皮细胞过度炎症反应的观点。尽管 CF 患者的肺部有丰富的促炎细胞因子和趋化因子，但由于肺部充满了免疫细胞和上皮细胞，无法预先知道 CF 肺部中的气道上皮细胞与非 CF 肺部上皮细胞相比，对铜绿假单胞菌的反应是否过度炎症。因此，体外研究人呼吸道上皮细胞系和原代细胞，提出研究 CFTR 基因突变对铜绿假单胞菌炎症反应的影响，对于 CF 具有不确定的临床意义。
