Abstract
AbstractPrevious analysis of CFTR-knockout (CFTR−/−) in piglets has provided important insights into the pathology of cystic fibrosis. However, controversies exist as to the true contribution of CFTR to the pH balance in airways and intestine. We therefore compared ion transport properties in newborn wild-type (CFTR+/+) and CFTR-knockout (CFTR−/− piglets). Tracheas of CFTR−/− piglets demonstrated typical cartilage malformations and muscle cell bundles. CFTR−/− airway epithelial cells showed enhanced lipid peroxidation, suggesting inflammation early in life. CFTR was mainly expressed in airway submucosal glands and was absent in lungs of CFTR−/− piglets, while expression of TMEM16A was uncompromised. mRNA levels for TMEM16A, TMEM16F, and αβγENaC were unchanged in CFTR−/− airways, while mRNA for SLC26A9 appeared reduced. CFTR was undetectable in epithelial cells of CFTR−/− airways and intestine. Small intestinal epithelium of CFTR−/− piglets showed mucus accumulation. Secretion of both electrolytes and mucus was activated by stimulation with prostaglandin E2 and ATP in the intestine of CFTR+/+, but not of CFTR−/− animals. pH was measured inside small bronchi using a pH microelectrode and revealed no difference between CFTR+/+ and CFTR−/− piglets. Intracellular pH in porcine airway epithelial cells revealed only a small contribution of CFTR to bicarbonate secretion, which was absent in cells from CFTR−/− piglets. In contrast to earlier reports, our data suggest a minor impact of CFTR on ASL pH. In contrast, enhanced amiloride-sensitive Na+ absorption may contribute to lung pathology in CFTR−/− piglets, along with a compromised CFTR- and TMEM16A-dependent Cl− transport.
Funder
Deutsche Forschungsgemeinschaft
UK Cystic Fibrosis Trust
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Clinical Biochemistry,Physiology
Reference53 articles.
1. Ballard ST, Trout L, Mehta A, Inglis SK (2002) Liquid secretion inhibitors reduce mucociliary transport in glandular airways. Am J Phys Lung Cell Mol Phys 283:L329–L335
2. Benedetto R, Cabrita I, Schreiber R, Kunzelmann K (2019) TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB J 33:4502–4512
3. Benedetto R, Ousingsawat J, Cabrita I, Pinto M, Lerias J, Wanitchakool P, Schreiber R, Kunzelmann K (2019) Plasma membrane localized TMEM16 proteins are indispensable for expression of CFTR. J Mol Med 97:711–722
4. Benedetto R, Ousingsawat J, Wanitchakool P, Zhang Y, Holtzman MJ, Amaral M, Rock JR, Schreiber R, Kunzelmann K (2017) Epithelial chloride transport by CFTR requires TMEM16A. Sci Rep 7:12397
5. Billet A, Hanrahan JW (2013) The secret life of CFTR as a calcium-activated chloride channel. J Physiol 591:5273–5278
Cited by
18 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献