Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Am J Physiol Lung Cell Mol Physiol. 2012 Aug 15;303(4):L327-33. doi: 10.1152/ajplung.00058.2012. Epub 2012 Jun 8.
The airway is kept sterile by an efficient innate defense mechanism. The cornerstone of airway defense is mucus containing diverse antimicrobial factors that kill or inactivate pathogens. Most of the mucus in the upper airways is secreted by airway submucosal glands. In patients with cystic fibrosis (CF), airway defense fails and the lungs are colonized by bacteria, usually Pseudomonas aeruginosa. Accumulating evidence suggests that airway submucosal glands contribute to CF pathogenesis by failing to respond appropriately to inhalation of bacteria. However, the regulation of submucosal glands by the innate immune system remains poorly understood. We studied the response of submucosal glands to the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α. These are released into the airway submucosa in response to infection with the bacterium P. aeruginosa and are elevated in CF airways. Stimulation with IL-1β and TNF-α increased submucosal gland secretion in a concentration-dependent manner with a maximal secretion rate of 240 ± 20 and 190 ± 40 pl/min, respectively. The half maximal effective concentrations were 11 and 20 ng/ml, respectively. The cytokine effect was dependent on cAMP but was independent of cGMP, nitric oxide, Ca(2+), or p38 MAP kinase. Most importantly, IL-1β- and TNF-α-stimulated secretion was blocked by the CF transmembrane conductance regulator (CFTR) blocker, CFTRinh172 (100 μmol/l) but was not affected by the Ca(2+)-activated Cl(-) channel blocker, niflumic acid (1 μmol/l). The data suggest, that during bacterial infections and resulting release of proinflammatory cytokines, the glands are stimulated to secrete fluid, and this response is mediated by cAMP-activated CFTR, a process that would fail in patients with CF.
气道通过有效的先天防御机制保持无菌。气道防御的基石是含有多种杀菌或失活病原体的抗菌因子的黏液。上气道的大部分黏液由气道黏膜下腺分泌。在囊性纤维化 (CF) 患者中，气道防御失败，肺部被细菌定植，通常是铜绿假单胞菌。越来越多的证据表明，气道黏膜下腺由于未能对细菌吸入做出适当反应而导致 CF 发病机制失败。然而，先天免疫系统对黏膜下腺的调节仍知之甚少。我们研究了黏膜下腺对促炎细胞因子白细胞介素-1β和肿瘤坏死因子-α的反应。这些细胞因子在细菌铜绿假单胞菌感染时被释放到气道黏膜下，并在 CF 气道中升高。IL-1β 和 TNF-α 的刺激以浓度依赖性方式增加黏膜下腺分泌，最大分泌率分别为 240±20 和 190±40 pl/min。半最大有效浓度分别为 11 和 20 ng/ml。细胞因子的作用依赖于 cAMP，但不依赖于 cGMP、一氧化氮、Ca(2+)或 p38 MAP 激酶。最重要的是，IL-1β 和 TNF-α 刺激的分泌被 CF 跨膜电导调节剂 (CFTR) 阻滞剂 CFTRinh172（100 μmol/l）阻断，但不受 Ca(2+)激活的 Cl(-)通道阻滞剂尼氟灭酸 (1 μmol/l)的影响。这些数据表明，在细菌感染和由此产生的促炎细胞因子释放期间，腺体被刺激分泌液体，这种反应由 cAMP 激活的 CFTR 介导，这一过程在 CF 患者中会失败。
