CFTR Gene Expression: Controlled by Cell Hypoxia By Dr. Artour Rakhimov - Last updated on August 9, 2018
Recent microbiological studies suggested that HIF-1 (hypoxia-inducible
factor-1 representing oxygen
availability) controls the expression of cystic fibrosis transmembrane
conductance regulator (CFTR) mutation gene.
American researchers from the Department of Medicine at the University of
Alabama (Birmingham, USA) tested the effects of cell oxygen levels on CFTR in
vitro. The title of their article in the American Journal of Physiology and
Cell Physiology, states that Improved oxygenation promotes CFTR
maturation and trafficking in MDCK monolayers (Bebk et al, 2001). In their
abstract, the researchers wrote, "Together, our data indicate that improved
cellular oxygenation can increase endogenous CFTR maturation and/or
In 2008, another group of US scientists from Alabama (Department of Genetics,
Fleming James Cystic Fibrosis Research Center, the University of Alabama at
Birmingham) investigated the Role of oxygen availability in CFTR expression
and function (Guimbellot et al, 2008). In the abstract, they wrote, "... In
the present study, we investigated the regulation of CFTR mRNA during oxygen
restriction, examined effects of hypoxic signaling on chloride transport across
cell monolayers, and related these findings to a possible role in the
pathogenesis of chronic hypoxic lung disease. CFTR mRNA, protein, and function
were robustly and reversibly altered in human cells in relation to hypoxia. In
mice subjected to low oxygen in vivo, CFTR mRNA expression in airways,
gastrointestinal tissues, and liver was repressed. CFTR mRNA expression was also
diminished in pulmonary tissues taken from hypoxemic subjects at the time of
lung transplantation. Environmental factors that induce hypoxic signaling to
regulate CFTR mRNA and epithelial Cl(-) transport in vitro and in vivo."
One year later, German scientists from the Department of Gastroenterology,
Hepatology, and Endocrinology at the Hanover Medical High School also confirmed
the effect of Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal
epithelium (Zheng et al, 2009). They wrote, " ... Consequently, HIF-1
overexpressing cells exhibited significantly reduced transport capacity in
colorimetric Cl(-) efflux studies, altered short circuit measurements, and
changes in transepithelial fluid movement. Whole-body hypoxia in wild-type mice
resulted in significantly reduced small intestinal fluid and HCO(3)(-) secretory
responses to forskolin. Experiments performed in Cftr(-/-) and Nkcc1(-/-) mice
underlined the role of altered CFTR expression for these functional changes, and
work in conditional HIF-1 mutant mice verified HIF-1-dependent CFTR regulation
in vivo. In summary, our study clarifies CFTR regulation and introduces the
concept of a HIF-1-orchestrated response designed to regulate ion and fluid
movement across hypoxic intestinal epithelia".
Other studies unrelated to cystic fibrosis showed that
low oxygen levels decrease active transport of sodium, chloride, and water across
primary epithelial cells in a dose-dependent
manner (Clerici and Matthay, 2000; Karle et al, 2004; Mairbaurl et
al, 1997; Mairbaurl et al, 2002).
What makes the CFTR gene expressed?
What is the cause of tissue hypoxia in people with cystic fibrosis?
medical studies proved that patients with CF suffer from chronic
alveolar hyperventilation that causes cell hypoxia. Chronic hyperventilation
generates an array of pathological changes in all vital organs. Most of all,
overbreathing reduces oxygen levels in body cells and this is the main effect of
hyperventilation on a cell level. (For details of reduced oxygen delivery to
cells, see the links below.)
Therefore, we can now state that reduced oxygenation of cells caused by
chronic hyperventilation plays the
crucial role in triggering CFTR mutation gene abnormalities and the development and pathogenesis of
Over 180 Russian and Ukrainian medical doctors applied the Buteyko breathing
technique and Frolov breathing device therapy on numerous people with cystic fibrosis. They found that breathing parameters predict their clinical picture
and symptoms for this health condition. Breathing normalization restores normal
health. Hundreds of people with cystic fibrosis have a normal life due to
breathing retraining that is used as a supplementary therapy in the complex
management of cystic fibrosis.
Clinical References: Cystic Fibrosis and Cell Hypoxia.
Bebk Z, Tousson A, Schwiebert LM, Venglarik CJ, Improved oxygenation promotes CFTR maturation and trafficking in MDCK monolayers, Am J Physiol Cell Physiol. 2001 Jan; 280(1): C135-45.
Clerici C, Matthay MA, Hypoxia regulates gene expression of alveolar epithelial transport proteins,J Appl Physiol. 2000 May;88(5):1890-6
Guimbellot JS, Fortenberry JA, Siegal GP, Moore B, Wen H, Venglarik C, Chen YF, Oparil S, Sorscher EJ, Hong JS, Role of oxygen availability in CFTR expression and function, Am J Respir Cell Mol Biol. 2008 Nov; 39(5): 514-21.
Karle C, Gehrig T, Wodopia R, Haschele S, Kreye VA, Katus HA, Bartsch P, Mairbaurl H, Hypoxia-induced inhibition of whole cell membrane currents and ion transport of A549 cells, Am J Physiol Lung Cell Mol Physiol. 2004 Jun; 286(6): L1154-60
Mairbaurl H, Wodopia R, Eckes S, Schulz S, and Bartsch P, Impairment of cation transport in A549 cells and rat alveolar epithelial cells by hypoxia, Am J Physiol Lung Cell Mol Physiol 273, 1997: L797–L806,
Mairbaurl H, Mayer K, Kim KJ, Borok Z, Bartsch P, and Crandall ED, Hypoxia decreases active Na transport across primary rat alveolar epithelial cell monolayers, Am J Physiol Lung Cell Mol Physiol 282: 2002, L659–L665,
Zheng W, Kuhlicke J, Jackel K, Eltzschig HK, Singh A, Sjablom M, Riederer B, Weinhold C, Seidler U, Colgan SP, Karhausen J, Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium, FASEB J. 2009 Jan; 23(1): 204-13.
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