CFTR Gene Controlled by Cell Hypoxia (and Breathing Patterns)

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 (Bebök 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 is the cause of tissue hypoxia in people with cystic fibrosis?

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.

Kindle Book "Cystic Fibrosis: Defeated
With Natural Self-Oxygenation Methods"

You probably know that thick mucus is the main culprit in cystic fibrosis. It is caused by abnormal transport of ions (e.g., Na and Cl) and water across the mucosal layers. This thick mucus starts to harbor pathological bacteria and cause GI and respiratory infections. However, you probably do not know that transport of ions and active transport of water is controlled by O2 levels in cells. If O2 is low, then transport of chemicals is going to be defective. This effect was found in all people. CFTR gene just makes the whole picture worse. Therefore, cystic fibrosis develops when tiny pumps that transport chemicals to form mucus have too little oxygen. If you have normal O2 in cells, you will not develop CF symptoms and problems even if you have CFTR gene. It makes total common sense that oxygen is the key factor in active transport of ions and water across epithelial layers. Apart from this, low body O2 suppresses the immune system making respiratory and GI infections much worse. Therefore, the solution to cystic fibrosis is to restore normal body O2 content 24/7.  You can click on the book image to visit the Amazon Kindle store and get this book now.

The main features of this book: - over 160 relevant medical studies - cutting-edge research articles about the cellular causes of cystic fibrosis (low O2 pressure in cells of the body leading to malfunction of ionic pumps that transport ions and water across epithelial layers) - causes of low body oxygenation (ineffective breathing patterns) confirmed by numerous studies - crucial lifestyle factors that lead to ineffective breathing - the outline of the program to restore normal breathing and normal body oxygenation

YouTube video: Trailer of the Amazon Kindle Book "Cystic Fibrosis: Defeated with Higher Body O2"

Cystic Fibrosis Web Pages:
- CFTR Mutation Gene Is Triggered by Cell Hypoxia - Review of medical studies that discovered something that makes common sense: tiny pumps that transport ions across mucosal layers in the respiratory and GI tract require oxygen for their normal work
- Cystic Fibrosis Cause: Each and every study that measured breathing in people with CF found that they have ineffective breathing that reduces body O2
- Cystic Fibrosis in Lungs develops according to laws of physiology and due to effects of hyperventilation
- Cystic Fibrosis Symptoms nicely correlate with their parameters of automatic breathing: those who have faster and deeper breathing have less oxygen and worse symptoms
- Cystic Fibrosis Prognosis depends on one key factor: how they breathe 24/7
- Cystic Fibrosis Life Expectancy and Lung CO2 & Body Oxygenation
- Therapy For Cystic Fibrosis: Treatment with Breathing Retraining
- Cystic Fibrosis Treatment is currently missing its most important part: techniques that lead to breathing normalization and improved O2 concentrations in body cells

Reference Web Pages: Breathing norms, Medical Graphs and Tables about Breathing Rates (Minute Ventilation) and Body Oxygen in Healthy, Normal and Sick People
Breathing norms Parameters, graph, and description of the normal breathing pattern
6 breathing myths 6 myths about breathing and body oxygenation (prevalence: over 90%)
Hyperventilation Definitions of hyperventilation: their advantages and weak points
Hyperventilation Syndrome in the Sick. Table 1. Western scientific evidence about prevalence of CHV (chronic hyperventilation) in patients with various chronic conditions (34 medical studies)
Normal Minute Ventilation in Healthy Subjects: Easy and Light Breathing (14 Studies)
Hyperventilation Prevalence Present in Over 90% of Normal People (24 medical publications)
HV and hypoxia How and why deep breathing reduces oxygenation of cells and tissues of all vital organs
Body oxygen test How to measure your own breathing and body oxygenation (a simple DIY test)
Body oxygen in healthy Table 4. CP (body oxygen level) in healthy people (27 medical studies)
Body oxygen in sick Table 5. CP (body oxygen level) in sick people (14 medical studies)
Buteyko Table of Health Zones with clinical description of most common zones
Morning HV Morning hyperventilation effect or how and why critically ill people are most likely to die during early morning hours

References: CO2 Effects Web Pages
Vasodilation: CO2 expands arteries and arterioles facilitating perfusion (or blood supply) to all vital organs
The Bohr effect How and why oxygen is released by red blood cells in tissues
Cell Oxygen Levels and oxygen transport are controlled by alveolar CO2 and breathing
Oxygen Transport depends on breathing and these two effects (Vasoconstriction-Vasodilation and the Bohr effect) are parts of two diagrams that summarize influences of hypocapnia (low CO2 content in the blood and cells) on circulation and O2 delivery
Free Radical Generation takes place due to anaerobic cell respiration caused by cell hypoxia. Hence, antioxidant defenses of the human body are also regulated by CO2 and breathing
Inflammatory Response is controlled by breathing since hypoxia leads to or intensifies chronic inflammation through over-expression of the hypoxia-inducible factor 1, while normal breathing reduces these processes
Nerve stabilization takes place due to calmative or sedative effects of carbon dioxide in neurons or nerve cells
Muscle relaxation or relaxation of muscle cells is normal at high CO2, while hypocapnia causes muscular tension, poor posture and, sometimes, aggression and violence
Brochodilation - dilation of airways (bronchi and bronchioles) by carbon dioxide, and their constriction due to hypocapnia
CO2: Best Natural Cough Suppressant and "home remedy" since it calms urge-to-cough nerve receptors located in the tracheobronchial tree and larynx
Blood pH regulation and regulation of other bodily fluids
CO2: Lung Damage Healer: Elevated carbon dioxide prevents injury and promotes healing of lung tissues
CO2: Skin and Tissue Healer
Synthesis of Glutamine in the Brain, CO2 fixation, and other chemical reactions
CO2 myth "CO2 is a toxic waste gas" myth
Breathing control How is our breathing regulated? Why hypocapnia makes breathing uneven and erratic?

References cystic fibrosis and cell hypoxia (low oxygen levels)

Yeger H, Pan J, Fu XW, Bear C, Cutz E, Expression of CFTR and Cl(-) conductances in cells of pulmonary neuroepithelial bodies, Am J Physiol Lung Cell Mol Physiol. 2001 Sep;281(3):L713-21.
The pulmonary neuroendocrine cell system comprises solitary neuroendocrine cells and clusters of innervated cells or neuroepithelial bodies (NEBs). NEBs figure prominently during the perinatal period when they are postulated to be involved in physiological adaptation to air breathing. Previous studies have documented hyperplasia of NEBs in cystic fibrosis (CF) lungs and increased neuropeptide (bombesin) content produced by these cells, possibly secondary to chronic hypoxia related to CF lung disease...

Zheng W, Kuhlicke J, Jäckel K, Eltzschig HK, Singh A, Sjöblom 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.
Diarrhea is widespread in intestinal diseases involving ischemia and/or hypoxia. Since hypoxia alters stimulated Cl(-) and water flux, we investigated the influence of such a physiologically and pathophysiologically important signal on expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Located on the apical membrane, this cAMP-activated Cl(-) channel determines salt and fluid transport across mucosal surfaces. Our studies revealed depression of CFTR mRNA, protein, and function in hypoxic epithelia. Chromatin immunoprecipitation identified a previously unappreciated binding site for the hypoxia inducible factor-1 (HIF-1), and promoter studies established its relevance by loss of repression following point mutation. 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 Hif1a 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.

Bebök 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.
Culturing airway epithelial cells with most of the apical media removed (air-liquid interface) has been shown to enhance cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl(-) secretory current. Thus we hypothesized that cellular oxygenation may modulate CFTR expression. We tested this notion using type I Madin-Darby canine kidney cells that endogenously express low levels of CFTR. Growing monolayers of these cells for 4 to 5 days with an air-liquid interface caused a 50-fold increase in forskolin-stimulated Cl(-) current, compared with conventional (submerged) controls. Assaying for possible changes in CFTR by immunoprecipitation and immunocytochemical localization revealed that CFTR appeared as an immature 140-kDa form intracellularly in conventional cultures. In contrast, monolayers grown with an air-liquid interface possessed more CFTR protein, accompanied by increases toward the mature 170-kDa form and apical membrane staining. Culturing submerged monolayers with 95% O(2) produced similar improvements in Cl(-) current and CFTR protein as air-liquid interface culture, while increasing PO(2) from 2.5% to 20% in air-liquid interface cultures yielded graded enhancements. Together, our data indicate that improved cellular oxygenation can increase endogenous CFTR maturation and/or trafficking.

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.
The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis; its absence leads to destruction of exocrine tissues, including those of the gastrointestinal tract and lung. Acute regulation of CFTR protein in response to environmental stimuli occurs at several levels (e.g., ion channel phosphorylation, ATP hydrolysis, apical membrane recycling). However, less information is available concerning the regulatory pathways that control levels of CFTR mRNA. 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.

Clerici C, Matthay MA, Hypoxia regulates gene expression of alveolar epithelial transport proteins, J Appl Physiol. 2000 May;88(5):1890-6.

Karle C, Gehrig T, Wodopia R, Höschele S, Kreye VA, Katus HA, Bärtsch P, Mairbäurl 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.
In excitable cells, hypoxia inhibits K channels, causes membrane depolarization, and initiates complex adaptive mechanisms... These results indicate that hypoxia, membrane depolarization, and K-channel inhibition decrease whole cell membrane currents and transport activity. It appears, therefore, that a hypoxia-induced change in membrane conductance and membrane potential might be a link between hypoxia and alveolar ion transport inhibition.

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:
L659–L665, 2002.

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: L797–L806, 1997.

Planes C, Escoubet B, BlotChabaud M, Friedlander G, Farman N, and Clerici C, Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells, Am J Respir Cell Mol Biol 17: 508–518, 1997.

Wodopia R, Ko HS, Billian J, Wiesner R, Ba¨rtsch P, and Mairbaurl, H. Hypoxia decreases proteins involved in transepithelial electrolyte transport of A549 cells and rat lung, Am J Physiol Lung Cell Mol Physiol 279: L1110–L1119, 2000.

Am J Clin Nutr 1999;69:913–9.
Energy expenditure and substrate utilization in adults with cystic fibrosis and diabetes mellitus
Ward SA, Tomezsko JL, Holsclaw DS, Paolone AM
... Results: In all 3 periods, minute ventilation was higher in the CF and CFDM groups than in the control subjects (P < 0.01).

Chest. 1990 Jun;97(6):1317-21.
Importance of respiratory rate as an indicator of respiratory dysfunction in patients with cystic fibrosis.
Browning IB, D'Alonzo GE, Tobin MJ.
... Respiratory frequency was increased in the patients with cystic fibrosis compared with a group of healthy control subjects, as was minute ventilation and mean inspiratory flow. Respiratory frequency was a sensitive predictor of respiratory dysfunction, being significantly (p less than 0.05) correlated with airway obstruction (r = 0.76), hyperinflation (r = 0.52), arterial oxygenation (r = -0.59), rib cage-abdominal discoordination (r = 0.54), and maximum ventilation during exercise (r = 0.66).

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