Cystic Fibrosis Symptoms/Stages Correlate with Cellular O2
As it was considered on other web pages, dysregulation in the work of the CFTR mutation gene are caused by low levels of oxygen in body cells. This conclusion was independently tested and confirmed by three teams of scientists from the USA and Germany (see the link to these studies below). These teams also found that the degree of CFTR mutation gene abnormalities is proportional to the level of tissue hypoxia and these abnormalities are expressed in cystic fibrosis symptoms.
Over 200 Russian doctors tested hundreds of people with CF and found that their body O2 content accurately reflects their health. Let us consider details of this dysregulation, or effects of cell hypoxia on symptoms and stages of cystic fibrosis.
Initial symptoms of cystic fibrosis
Clinical evidence of more than 100 Russian medical doctors teaching breathing retraining (the Buteyko method and Frolov respiration device) have found that the initial or very mild symptoms of CF and abnormalities in the work of the CFTR protein are triggered when the body oxygen level is below 30 s. (We assume here that the person with cystic fibrosis previously had normal body-oxygen levels and, as a result, he or she did not experience any negative symptoms.) This stage is accompanied by the appearance and dominance of pathogens in the GI tract with light symptoms in pulmonary and hormonal areas.
Mild or moderate symptoms (stage 2) of cystic fibrosis
Many web pages of this website refer to 20 s threshold for the body-oxygen test as a very significant number. It corresponds to appearance of numerous physiological and biochemical abnormalities in the human body, including cell hypoxia, suppression of the immune system, problems with protein metabolism and synthesis of various fundamental substances, including hormones and neurotransmitters and many others.
In relation to airways, overbreathing causes chronic inflammation, mucociliary dysfunction, generation of extra mucus (as in asthma and bronchitis), appearance of allergic reactions and bronchoconstriction. The effects are mostly triggered by hypocapnia (or CO2 deficiency).
It is suggested here that abnormal breathing parameters affect the mutated CFTR protein, which is responsible for synthesis of a protein that functions as a channel for chloride ions and is controlled by cyclic adenosine monophosphate. Mutations in the transmembrane conductance regulator gene causes abnormalities of chloride transport across mucosal surfaces. Defective CFTR gene causes diminished secretion of chloride ions and increased reabsorption of Na and water across the epithelial cells. This causes mucus that is thicker and stickier to bacteria.
More severe symptoms (stage 3) of cystic fibrosis
Increased inflammation and pathological load on the human organism due to infections further intensify breathing in people with cystic fibrosis. Later stages are characterized by less than 10 s CP during early morning hours (the patient has less than 10 s of oxygen in the body; that means they breathe about 4 times more than the tiny medical norm) or transition to the pre-final stage in the Buteyko Table of Health Zones.
With less than 10 s CP, even human blood does not resist the spread of various infections and the whole clinical picture quickly deteriorates. Involvement in the respiratory system becomes progressive: bronchitis and bronchiolitis transform into bronchiectasis. Possible complications include hemoptysis and pneumothorax. Severe dyspnea, strong chest pain and difficulty breathing are frequent complaints. The clinical picture is worsened by severe abnormalities in CFTR work.
Severe hyperventilation also promotes development of complication due to diabetes.
The last stage (stage 4)
With less than 5 s CP, as the Buteyko Table of Health Zones suggests, patients with cystic fibrosis enter into the zone where they fight with death. Severe alveolar hyperventilation leads to critically low CO2 levels in airways with frequent development of cor pulmonale (high blood pressure in the pulmonary arteries and right heart overload). Such a 0 clinical picture is typical for the end-stage lung disease, which is the principal cause of death in most patients with CF.
Experience of Russian medical doctors with hundreds of people with cystic fibrosis suggests that it is possible to restore normal body-oxygen levels and move in the opposite direction: from the last stage to clinical remission and elimination of symptoms of cystic fibrosis.
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Thick mucus is the main culprit in cystic fibrosis. It is caused by the 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 the transport of ions and the active transport of water is controlled by O2 levels in cells. If O2 is low, then the transport of chemicals is going to be defective. This effect was found in all people. The 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 the CFTR gene.
It makes common sense that oxygen is the key factor in the 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:
YouTube video: Trailer of the Amazon Kindle Book " Cystic Fibrosis: Life Expectancy: 30, 50, 70..."
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 symptoms correlate with their parameters of automatic breathing: those who have faster and deeper breathing have less oxygen and worse symptoms
- Cystic fibrosis cause: Each and every study that measured the breathing in people with CF found that they have ineffective breathing, which reduces body O2
- Cystic fibrosis in lungs develops according to laws of physiology and due to effects of hyperventilation
- Cystic fibrosis prognosis depends on one key factor: how the person with CF breathes 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.
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
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):
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:
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).
Reference pages: Breathing norms and the DIY body oxygen test:
- Breathing norms: Parameters, graph, and description of the normal breathing pattern
- Body-oxygen test (CP test) : How to measure your own breathing and body oxygenation (two in one) using a simple DIY test
References: pages about CO2 effect:
- 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 body tissues
- Nerve stabilization: Carbon dioxide has powerful calmative and sedative effects on brain neurons and nerve cells
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