CFTR Gene Expression: Controlled by Cell Hypoxia
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, 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 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 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?
Minute ventilation in cystic fibrosis patients at rest
|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|
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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 heath condition. Breathing normalization restore normal health. Hundreds of people with cystic fibrosis have normal life due to breathing retraining that is used as a supplementary therapy in complex management of cystic fibrosis.
References: Cystic Fibrosis and Cell Hypoxia.
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