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缺陷,尤其是微生物的粘液清除缺陷。气道粘膜下腺体分泌大多数气道粘液,而CF气道腺体对VIP或forskolin不分泌。CFTR是CF中存在缺陷的蛋白质,在腺体中表达,但免疫细胞化学发现CFTR在纤毛导管或腺泡中表达最高,具体取决于所使用的抗体。CFTR是forskolin介导的腺体分泌绝对必需的; 我们使用这一发现来定位forskolin刺激的CFTR依赖性腺液分泌的起源。我们检验了以下假设: 毛喉素的分泌可能起源于腺管,而不是腺泡。我们在各个点结扎腺管,用forskolin刺激腺体,并监测肿胀的腺体区域。结果支持分泌的腺泡而不是导管起源。我们使用Nomarski延时成像技术跟踪了粘液中的颗粒; 颗粒起源于腺泡,并向导管口传播。估计的大量流量在腺泡和粘液小管中加速,与这些区域的液体分泌一致,但在无分支的导管中是恒定的,与导管上皮缺乏液体分泌或吸收相一致。我们得出结论,CFTR依赖性腺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是无法解释的,但可能表明该上皮改变了腺体粘液的组成而不是体积。

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