Respiratory gases and the regulation of transcription

Eoin P. CumminsCiara E. KeoghFirst published: 30 July 2016

New Findings

  • What is the topic of this review?This review highlights the transcriptional consequences for decreased cellular O2 levels (hypoxia) and increased cellular CO2 levels (hypercapnia).
  • What advances does it highlight?We discuss recent advances in our understanding of the cellular response to hypoxia and consider the potential cross-talk between O2– and CO2-dependent transcriptional regulation.

Oxygen and carbon dioxide are the substrate and product of aerobic metabolism, respectively. Thus, the levels of these physiological gases are inextricably linked in physiological and pathophysiological conditions. Increased mitochondrial consumption of O2 (to produce ATP) will produce more CO2. Furthermore, in lung pathologies such as chronic obstructive pulmonary disease, sleep apnoea and central hypoventilation syndrome, hypoxia and hypercapnia are co-incident. Acute responses to hypoxia involve carotid body-mediated changes in the rate and depth of breathing. Chronic adaptation to hypoxia involves a multitude of changes on a transcriptional level, which simultaneously increases oxygen utilization (via hypoxia-inducible factor and others), while suppressing superfluous energy-demanding processes. Acute responses to CO2 affect breathing primarily via central chemoreceptors. The nature of hypercapnia-dependent transcriptional regulation is an emerging area of research, but at present the mechanisms underpinning this response are not fully characterized and understood. Thus, given the juxtaposition of hypoxia and hypercapnia in health and disease, this manuscript reviews the current evidence for transcriptional responses to hypoxia and hypercapnia. Finally, we discuss the potential cross-talk between hypoxia and hypercapnia on a transcriptional level.

Dear Dr Cummns,
Thank you so much for your 2016 paper   “Respiratory gases and the regulation of transcription”. I am not a scientist or a doctor and I understand only the smallest gist of your ideas; but I have come across the finding made by early physiology pioneers that the range of respiratory rate at rest is very wide, from as low as 3 breaths per minute to as high as 30.

 The set point in these individuals has been altered from what is most practicable and effectives , making pH and C02 homeostasis more complex and less ideal in their cases, , especially in situations of exposure, hormonal changes and/or upper respiratory obstruction [ie.  cold] or all 3 at once.
Doctors are not aware of this any longer because they no longer measure respiratory rate except if one is in the intensive care unit because RR says little about the state of the lungs. It says a lot about the nervous system, though.

Abnormal RR does say something about possible tissue hypoxia and hypercapnic acidosis and pathophysiology during illness,or further injury and/or  physical weakness and the mechanical difficulty moving air in and out of the body, even with normal lungs.

My friend and colleague Paula has such a non progressive ventilatory defect. No one sees it unless they count her respirations carefully with a stopwatch. She is not aware of it. She feels her breathing to be normal but it is not. She uses active exhaling with every breath in order to increase her tidal volume.
In her 66 healthy years since her difficult birth, she has only had one yearlong hypercapnic respiratory failure episode. [we assume this is what it was].

She experienced what we now understand to be the anguish of unexplained dyspnea, when she could not raise her RR at rest when ill and in fact, her RR declined to 2.5 breaths per minute.
Over 100 years ago, a very famous researcher found respiratory depression [no drugs, no yoga] in thousands of patients who’d suffered from quiet insanity and anguish.  They did not die and this in and of itself was interesting. They, like Paula, took a long time to recover.   All had periods of spontaneous recovery of physical and mental health, although without treatment, they might be sick for months, years, decades before remitting.  The researcher who followed them was fascinated.
I know that you are not a doctor, but understanding the altered mechanical set points of moving air in and out of the body, affecting respiratory gases,  is  part of physiology. Understanding  the process of genes being turned on and off , especially at birth, due to experiences like hypoxia or anoxia during life and its consequences biologically is fascinating. 

What changed in Paula ,when she got stuck in a birth canal distorted by Rickets [a deficiency disease caused by poverty]. and was suctioned [swallowed meconium], resuscitated and transfused.  Did that alter her set point for breathing? What else was changed as a result of this near death experience? How come no one noticed?

How is it that Paula is even alive, how did she survive childhood diseases like measles and whooping cough?

She married well, had children, who themselves had kids and she has a successful career. And we talk every day [over zoom].

She survived because of the biology stuff you describe and hypothesize in your fabulous paper.
I read that many neurological and neuropsychiatric patients have abnormal set points, respiratory rate being too slow or too fast or irregular at rest.

It is a shame that scientists and doctors are not learning about health and illness in patients who’s “set points” in RR have changes due to injury [non progressive] to the throat, neck, or torso, nerve fibres, ganglion, rib attachments, etc…].

Maybe it is time for some interdisciplinary biological research to learn more about the various phenotypes like that of Paula, that emerge after surviving near death circumstances and end up surviving and surviving well or succumbing to neurological illness later on in life. .

I think it is fascinating.I hope you think it is fascinating as well. .

Please share these ideas with others.  {warning; you will find very little interest in “control of breathing ” issues amongst Doctors and a lot of ignorance about biology.]



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