Grubb B R, Gabriel S E
Cystic Fibrosis/Pulmonary Research and Clinical Treatment Center, University of North Carolina, Chapel Hill 27599, USA.
Am J Physiol. 1997 Aug;273(2 Pt 1):G258-66. doi: 10.1152/ajpgi.1997.273.2.G258.
Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.
囊性纤维化（CF）是一种致命的遗传性疾病，每2500例白人新生儿中约有1例受其影响。该疾病可被描述为一种影响多种上皮组织的全身性外分泌疾病，在大量新生儿中早期表现为胎粪性肠梗阻。导致CF的基因于1989年被克隆出来，其蛋白质产物囊性纤维化跨膜传导调节因子（CFTR）已被确凿证明是一种受3',5'-环磷酸腺苷（cAMP）调节的氯离子通道。随后，通过基因靶向方法建立了几种CF小鼠模型，试图进一步了解这种疾病。这些小鼠模型的出现最初带来的兴奋之情，因发现没有一个模型出现气道疾病而有所缓和，而气道疾病目前是人类CF患者群体中大多数发病和死亡的原因。然而，目前有10种不同的CF小鼠模型，它们在肠道病理生理学方面与人类非常相似。最重要的是，CF小鼠模型的肠道显示出缺乏cAMP介导的氯离子转运，这是CF疾病的一个标志。此外，CF小鼠肠道还表现出无法分泌碳酸氢根、电中性氯化钠吸收的cAMP调节缺陷、远端结肠中电生性钠离子转运增加以及其他离子转运紊乱。除了在CF小鼠肠道中研究的离子转运基本机制外，这些模型在理解CF相关的其他组织方面也很重要。CFTR基因敲除杂合子小鼠分泌氯离子和液体的能力降低，因此为CF“杂合子优势”假说提供了进一步支持。一些CF小鼠模型仍保持有限的分泌氯离子能力，这可能是由于推测存在辅助基因，可减轻这些小鼠肠道中的疾病严重程度。本综述描述了所建立的CF模型，并将小鼠的离子转运缺陷与人类CF肠道中观察到的异常进行了比较。
