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Cystic Fibrosis Prognosis Depends on Body-Oxygen Levels

Doctor provides cystic fibrosis prognosisCystic fibrosis abnormalities and symptoms cannot exist or appear in conditions of normal body oxygenation. This was proven in several medical studies related to function of the CFTR (cystic fibrosis transmembrane conductance regulator) gene (Bebk et al, 2001; Guimbellot  et al, 2008; Yeger et al, 2001; Zheng et al, 2009).

Oxygen tensions in cells directly influence ionic pumps that transmit ions of chloride and sodium, water and other substances across the epithelium. All cells require oxygen for normal function. It is especially true for those cells and protein complexes that are involved in constriction (mitochondria) or active transport of substances (transport of ions in epithelium).

There are also independent studies unrelated to cystic fibrosis prognosis that showed that efficiency of ionic pumps in lungs depends on oxygen levels in a dose-dependent manner (Clerici & Matthay, 2000; Karle et al, 2004; Mairbaurl et al, 1997; Mairbaurl et al, 2002).

What are the causes of low body oxygenation 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

Medical studies that measured respiratory parameters found that CF patients suffer from chronic hyperventilation (breathing more than the medical norm). Overbreathing leads to alveolar hypocapnia (low CO2 levels in the lungs) which destroys the tissue of the lungs (see Cystic Fibrosis in Lungs). Minute ventilation in CF patients in these 7 medical studies ranged from 10 to 18 Liters per minute at rest (adjusted to 70-kg normal weight), while the medical norm is only 6 L/min.

Hence, low body-oxygen levels are caused by hyperventilation which worsens lung function and increases patient's complaints about dyspnea (breathlessness) and inability to exercise. Therefore, breathing parameters predict stages, prognosis, and life expectancy in cystic fibrosis.

Medical research has conclusively proven that chronic hyperventilation have numerous negative effects on all systems and organs, including destruction of lungs tissue, more problems with digestion and blood sugar control and many others. Fortunately, a large group of over 180 Russian MDs have developed and applied a breathing therapy for cystic fibrosis and revealed the following relationships between respiratory parameters and life expectancy or prognosis in CF patients.

Cystic fibrosis prognosis (chart)

Stages, life expectancy and prognosis for cystic fibrosis patients and their respiratory parameters
Respiratory frequency Alveolar CO2 Body-oxygen level Stages of the disease Usual life
Symptoms and prognosis
> 30 breaths/min <3.5% 1-5 seconds End-stage disease Some months Quickly developing and severe problems with lungs (possible cor pulmonale), chronic indigestion, etc.
26-30 breaths/min 3.5-4.0% 6-10 s Clinical stage (hospitalization or
palliative care is required)
Less than 1-2 years Worsened health state with progressive respiratory deterioration: bronchitis and bronchiolitis transform into bronchiectasis; possible complications include hemoptysis and pneumothorax.
20-26 breaths/min 4.0-4.5% 11-20 s Moderate individual symptoms Up to 30-40 years A typical patient with classical symptoms of mild cystic fibrosis including chronic infections, poor exercise tolerance, inflammation, GI symptoms, ...
12-20 breaths/min 4.5-5.5% 20-40 s Initial stage of the disease Up to 40-60 years Mild GI symptoms; slight deterioration in lung function tests
< 12 breaths/min >5.5% over 40 s 24/7 Normal health Normal No symptoms, normal life expectancy

Damage to lungs, sinuses, pancreas, liver, intestines, and sex organs in cystic fibrosis is proportional to degree of pulmonary abnormalities, while a complete clinical remission in patients with cystic fibrosis takes place in cases of normalization of outer respiration. Patients with cystic fibrosis have an excellent prognosis and normal life expectancy if they can normalize their respiratory pattern.

Bear in mind that cystic fibrosis prognosis depends on processes in the lungs and alveoli. As a result, development of this medical condition leads to increased ventilation-perfusion mismatch and problems with effective gas exchange. Another practical aspect related to cystic fibrosis is that for overwhelming majority of CF patients, the lowest body oxygenation and heaviest breathing (or worst respiratory parameters) take place during early morning hours (or the last portion of the night sleep) due to the Sleep Heavy Breathing Effect (or nocturnal hypoxemia). Obviously, the morning CP (body-oxygen test - see below) is the main easy-to-measure parameter that influences prognosis, stages, life expectancy and quality of life in CF patients.

Kindle Book - Cystic Fibrosis Life Expectancy: 30, 50, 70, ...

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.

Cystic fibrosis symptoms (book cover)

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 the 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

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 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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