CFTR Gene Expression: Controlled by Cell Hypoxia

- Updated on August 1, 2019

CFTR Gene Expression: Controlled by Cell Hypoxia 1By Dr. Artour Rakhimov, Alternative Health Educator and Author


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 trafficking”.

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.”

Young MDs 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?

Minute ventilation in cystic fibrosis patients at rest

Condition Minute
Number of
Normal breathing 6 L/min Medical textbooks
Healthy subjects 6-7 L/min >400 Results of 14 studies
Cystic fibrosis 15 L/min 15 Fauroux et al, 2006
Cystic fibrosis* 13 (�2) L/min 10 Bell et al, 1996
Cystic fibrosis 10 L/min 11 Browning et al, 1990
Cystic fibrosis 11-14 L/min 6 Tepper et al, 1983
Cystic fibrosis* 10 L/min 10 Ward et al, 1999
CF and diabetes* 10 L/min 7 Ward et al, 1999
Cystic fibrosis 16 L/min 7 Dodd et al, 2006
Cystic fibrosis 18 L/min 9 McKone et al, 2005
Click here for all Cystic Fibrosis References

Cystic fibrosis patients These 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 cystic fibrosis.

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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