Bioelectric properties of chloride channels in human, pig, ferret, and mouse airway epithelia.
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-CF transmembrane conductance regulator (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, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS)-sensitive Cl(-) transport, and cAMP-sensitive Cl(-) transport. In addition, as an index for CFTR functional conservation, we evaluated the ability of four CFTR inhibitors, including glibenclamide, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, CFTR (inh)-172, and CFTR(inh)-GlyH101, to block cAMP-mediated Cl(-) transport. Compared with 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.
Liu
Xiaoming
X
Department of Anatomy, The Center for Gene Therapy, College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Luo
Meihui
M
Zhang
Liang
L
Ding
Wei
W
Yan
Ziying
Z
Engelhardt
John F
JF
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004553:Electric Conductivity; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005289:Ferrets / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013552:Swine / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014132:Trachea / Q000166:cytology
D018118:Chloride Channels; D049990:Membrane Transport Modulators; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP