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: |
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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).
Reference pages: Breathing norms and medical facts:
-
Breathing
norms: Parameters, graph, and description of the normal
breathing pattern
- 6 breathing myths: Myths and superstitions about breathing
and body oxygenation (prevalence: over 90%)
- Hyperventilation: Definitions of
hyperventilation: their advantages and weak points
- Hyperventilation syndrome:
Western scientific evidence about prevalence of chronic hyperventilation in patients with chronic conditions
(37 medical studies)
- Normal minute ventilation: Small and
slow
breathing at rest is enjoyed by healthy subjects (14 studies)
- Hyperventilation prevalence: Present in
over 90% of
normal people (24 medical studies)
- HV and hypoxia:
How and why deep breathing reduces oxygenation of cells and tissues of
all vital organs
- Body-oxygen test (CP test)
: How to measure your own breathing and body oxygenation (two in one) using a simple DIY test
- Body oxygen in healthy:
Results for the body-oxygen test for healthy people (27 medical
studies)
- Body oxygen in sick
: Results for the body-oxygen test for sick people (14 medical studies)
- Buteyko
Table of Health Zones: Clinical description and ranges for breathing zones:
from the critically ill (severely sick) up to super healthy people
with maximum possible body oxygenation
- Morning hyperventilation: Why people feel
worse and critically ill people are most
likely to die during early morning hours
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 tissues
- Cell oxygen levels: How alveolar CO2 influences
oxygen transport
- Oxygen transport: O2 transport is controlled by
vasoconstriction-vasodilation and the Bohr effects, both of which rely on CO2
- Free radical generation:
Reactive oxygen species are produced within cells due to anaerobic cell respiration caused by cell hypoxia
- Inflammatory response: Chronic inflammation
in fueled by the hypoxia-inducible factor 1, while normal breathing reduces
and eliminates inflammation
- Nerve stabilization: People remain calm due to calmative or
sedative effects of carbon dioxide in neurons or nerve cells
- Muscle relaxation: Relaxation of muscle cells
is normal at high CO2, while hypocapnia causes muscular tension, poor posture
and, sometimes, aggression and violence
- Bronchodilation: Dilation of
airways (bronchi and bronchioles) is caused by carbon dioxide, and their constriction
by hypocapnia (low CO2)
- Blood
pH: Regulation of blood pH due to breathing and regulation of other bodily fluids
- CO2: lung damage: Elevated carbon
dioxide prevents lung injury and promotes healing of lung tissues
- CO2: Topical carbon dioxide can heal skin and tissues
- Synthesis of glutamine
in the brain, CO2 fixation, and other chemical reactions
- Deep breathing myth:
Ignorant and naive people promote the idea that deep breathing and breathing
more air at rest is beneficial for health
- Breathing control: How is our
breathing regulated? Why hypocapnia makes breathing uneven, irregular and erratic.
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