Published ahead of print on September 28, 2006, doi:10.1165/rcmb.2006-0286OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 3, March 2007, 313-323 A more recent version of this article appeared on March 1, 2007
Submitted on August 7, 2006 Bioelectric Properties of Chloride Channels in Human, Pig, Ferret and Mouse Airway EpitheliaXiaoming Liu1,1 Departments of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA; The Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa, College of Medicine, Iowa City, Iowa, USA, 2 Departments of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA, 3 Departments of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA; Department of Internal Medicine, University of Iowa, College of Medicine, Iowa City, Iowa, USA; The Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa, College of Medicine, Iowa City, Iowa, USA * To whom correspondence should be addressed. E-mail: john-engelhardt{at}uiowa.edu.
The development of effective therapies for cystic fibrosis (CF) requires animal models that can appropriately reproduce the human disease phenotype. CF mouse models have demonstrated cAMP-inducible, non-CFTR chloride transport in conducting airway epithelia, and this property is thought to be responsible for the lack of a spontaneous CF-like phenotype in the lung. Thus, an understanding of species diversity in airway epithelial electrolyte transport and CFTR function is critical to developing better models for CF. Two species currently being used in attempts to develop better animal models of CF include the pig and ferret. In the study reported here, we sought to comparatively characterize the bioelectric properties of in vitro polarized airway epithelia -from human, mouse, pig and ferret- grown at the air-liquid interface (ALI). Bioelectric properties analyzed include amiloride-sensitive Na+ transport, DIDS-sensitive Cl- transport, and cAMP-sensitive Cl- transport. Additionally, as an index for CFTR functional conservation, we evaluated the ability of four CFTR inhibitors, including glibenclamide, NPPB, CFTR inh-172 and CFTRinh-GlyH101, to block cAMP-mediated Cl- transport. In comparison to human epithelia, pig epithelia demonstrated enhanced amiloride-sensitive Na+ transport. In contrast, ferret epithelia exhibited significantly reduced DIDS-sensitive Cl- transport. Interestingly, although the four CFTR inhibitors effectively blocked cAMP -mediated Cl- secretion in human airway epithelia, each species tested demonstrated unique differences in its responsiveness to these inhibitors. These findings suggest the existence of substantial species-specific differences at the level of the biology of airway epithelial electrolyte transport, and potentially also in terms of CFTR structure/function.
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