Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na(+) channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus.

译文

囊性纤维化(CF)气道疾病源于先天防御能力不足,尤其是微生物清除粘液的能力不足。气道粘膜下腺分泌大多数气道粘液,而CF气道腺不响应VIP或毛喉素而分泌。 CFTR是CF中的缺陷蛋白,在腺体中表达,但免疫细胞化学发现CFTR在纤毛管或腺泡中的表达最高,具体取决于所使用的抗体。 CFTR是forskolin介导的腺体分泌所绝对必需的。我们利用这一发现来定位受福斯高林刺激的,依赖CFTR的腺体分泌液的起源。我们检验了福斯克林分泌可能起源于腺管而不是腺泡或除了腺泡之外的假说。我们结扎腺体的各个部位,用福司可林刺激腺体,并监测肿胀的腺体区域。结果支持腺泡而不是导管的分泌来源。我们使用Nomarski延时成像技术追踪了粘液中的颗粒。颗粒起源于腺泡,并朝着导管孔口行进。估计的腺泡和粘液小管中的总流量加速,与那些区域的液体分泌一致,但在未分支的导管中恒定,这与导管上皮缺乏液体分泌或吸收一致。我们得出结论,CFTR依赖的腺体液分泌起源于浆液性腺泡。无法观察到CFTR和富含上皮Na()通道(ENaC)的纤毛导管的分泌或吸收均无法解释,但可能表明该上皮改变了组成而不是腺黏液的体积。

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