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In: AIR POLLUTION: SOURCES, PREVENTION AND HEALTH EFFECTS. ISBN 978-1-62417-735-4
Editor: Rajat Sethi © 2013 Nova Science Publisher, INC.
Chapter 16
▬THE CO2 HYPOTHESIS▬
THE STRESS OF GLOBAL WARMING ON HUMAN HEALTH:
PH HOMEOSTASIS, THE LINKAGE BETWEEN BREATHING &
FEEDING VIA CO2 ECONOMY
Donatella Zappulla
Department of Experimental and Clinical Pharmacology,
University of Catania, School of Medicine, Catania, Italy
ABSTRACT
Global emissions od carbon dioxide (CO2) from burning fossil fuels have increased
by half in the last 20 years, giving the world much less chance of avoiding dangerous
climate changes, according to new data. Thus, in spite of the economic slowdown, and
despite the efforts by governments to reduce them, the amount of CO2 in the atmosphere
has reached ~391parts per million, or 140% of the pre-industrial level of ~280 ppmv.
The concentrations of CO2 in the atmosphere are however increasing only at about
half the rate of CO2 production. The remainder of the gas is taken up by the terrestrial
biosphere, stored on land, and sunk into the oceans as CO2 challenges pH homeostasis, a
key factor for the proper functioning of all living cells. Notably, earlier human studies
have shown that chronic exposure to CO2 at moderate inspired concentrations alters pH
homeostasis, and fosters the storage of CO2 in the body at the expense of buffer protein
and phosphate in lean body mass, as do increased atmospheric CO2 concentrations in the
terrestrial biosphere. Actually, higher CO2 stores matching lower bone mineralization
characterizes Osteoporosis, a major public health problem whose risks for osteopenia and
non-spine fractures are significantly higher for people with higher percentage of body fat.
Increased CO2 storage is present also in Obstructive Sleep Apnea, a prevalent disorder
characterized by gradual elevations of the partial pressure of CO2 in the arterial blood,
associated with major nocturnal hemoglobin desaturation, increased HbO2 affinity, and
repetitive episodes of partial or complete upper airway obstruction.
Most individuals with obstructive sleep apnea have Metabolic Syndrome, a common,
chronic condition characterized by the cluster of abdominal obesity with other risk factors
for atherosclerotic-cardiovascular disease (ACVD) that share abnormal intracellular ion
profile in red blood cells, and sustained cortisol levels, as it occurs with chronic exposure
Correspondence to: Dr. Donatella Zappulla, M.D. Viale Jonio 105, 95129 Catania, Italy; Telephone N°: 011-39-
095-372839; Email: doza83@virgilio.it; dz83@columbia.edu.
Donatella Zappulla, M.D.
2
to mildly increased ambient CO2. Studies suggest that moderately increased endogenous
CO2 may oxidize erythrocytes, and promote their suicidal death (eryptosis) which, by
fostering the release of pro-inflammatory cytokines throughout systemic circulation,
activates the hormonal stress response, and results in increased CO2 stores, abdominal fat
accumulation, and Metabolic Syndrome. Ominously, Global Warming is an unbearable
stress for ecosystems and their member species, just as this cluster of ACVD risk factors
is for human health. Atmospheric CO2 increase could, at least in theory, bears a main
impact on its pathogenesis, a possibility not explored yet in any extent. This review
focuses on Metabolic Syndrome and pH homeostasis, the linkage between breathing and
feeding via CO2 economy, to disclose the stress of global warming on human health.
Keywords: Atmospheric CO2 Increase; Erythrocyte Suicidal Death (Eryptosis); Stress; pH
Homeostasis; Ventilation; Food Intake; Metabolic Syndrome (MetS); Osteoporosis.
PREFACE
Once upon a time, before the advent of human-caused release of carbon dioxide (CO2)
into the atmosphere, CO2 concentrations tended to rise with increasing global temperatures,
acting as a positive feedback for changes induced by other natural processes. Around 400–
600 million years ago, atmospheric levels of CO2 in dry air ranged ≥ 6000ppmv (0.6%) [1].
Then, autotrophic (self-feeding) cells in plants (photosynthetic), and some bacteria, and
heterotrophic (feeding on others) cells of higher animals and most micro-organisms literally
fed each other. Through the cycling of carbon, oxygen (O2), and nitrogen, photosynthetic
cells produced organic compounds such as glucose, from atmospheric CO2, water (H2O), and
soil nitrogen, at the expense of solar energy. Heterotrophic cells used the organic compounds
produced by photosynthetic cells as fuels and building blocks; the CO2 formed as end-product
of their aerobic metabolism was, in turn, returned to the atmosphere to be used again by
photosynthetic cells [2,3]. As photosynthesis by reef benthos encouraged invasion of CO2
from the atmosphere, pH shifts favored the harvesting of CO2 as bicarbonate (HCO3-) and
carbonate (CO3-2) in the marine ecosystem. The vast CO2 stores in the deep ocean in turn
controlled the partial pressure of CO2 (PCO2) in the atmosphere [4]. Due to these biochemical
feedbacks, atmospheric concentrations of CO2 in dry air ranged ~284ppmv (0.0284%) in the
mid of 1800s [1,3].
Today, this wise strategy of Mother Nature is overwhelmed. Worldwide annual usage
rates of energy for industrial or domestic usage, transportation, and biomass burning have
increased about 20-fold since the beginning of the Industrial Revolution, in 1850, and 4.5
times since 1950 [5]. As a result, CO2 emissions have increased by one-third, and are still
rising at an unprecedented rate of an average 0.4% per year [6]. Current atmospheric CO2
concentrations range ~391ppmv (0.0391%), representing an increase of ~36% since the
advent of human industrial activity [7]. But the concentration of CO2 in the atmosphere has
increased only at about half the rate of its production.
The remaining CO2 has been taken up by the terrestrial biosphere and soil as CO2 at
concentrations higher than 0.03% induces an excess of photosynthesis over photorespiration
which fosters plant soil nitrogen uptake, slows down soil microbial respiration, and enhances
carbon accumulation on land [8]. Increasing amounts of CO2 also sink into the ocean and, as
photorespiration and calcification (reef rock formation) decline in parallel, adaptations in the
The Stress of Global Warming on Human Health
3
carbonate chemistry of the ocean [9] reduce formation of the calcareous skeleton of marine
vertebrates and planktonic organisms in reefs [10]. Hence, atmospheric CO2 concentrations
range ~0.0391% at the expense of the Earth’ backbone, which is losing its supporting
function as does an early aged, brittle osteoporotic skeleton [10,11].
INTRODUCTION
CO2 gas traps radiation (heat) within the Earth’s atmosphere causing it to warm thus, due
to its higher levels, the natural greenhouse effect that makes the Earth habitable is amplified
[7], and global surface temperature has raised by ~0.5°C. Since this burst of warming has
taken global temperature up to its highest level in the past millennium [12], increased glacial
melting fosters loss of wetlands together with seawater intrusion in freshwater sources, and
world population suffers from the depletion of many natural systems [6]. Beyond that, higher
atmospheric CO2 levels stress public health as taxing climate changes may “force” people to
spend the majority of their time in buildings, passenger cars, or other closed environments,
where the concentrations of CO2 correlated with human metabolic activity have been found to
be 20- up to 100-fold greater than in atmospheric air [13,14]. Earlier human studies have
shown that chronic, continuous exposure to CO2 at 0.5-3% inspired concentrations for more
than one month alters pH homeostasis and raises body CO2 storage [15,16,17], as does higher
atmospheric CO2 concentration in the terrestrial biosphere.
Mostly during CO2 exposure, ion profile changes in red blood cells (RBCs); hemoglobin-
O2(HbO2) affinity increases with RBCs oxidation; the adrenal cortical response is activated,
as measured by increased blood corticosteroid level and lymphopenia; and the partial pressure
of CO2 in the arterial blood (PaCO2) rises as CO2 is stored as HCO3- in the extracellular fluid
(ECF), and as CO3-2 in bone, at the expense of buffer protein and phosphate in the lean body
mass (LBM) [15,16,17]. Continuous CO2 inhalation is commonly thought to be tolerated at
3% inspired concentrations for at least one month, and 4% inspired concentrations for over a
week. The effects produced seem reversible, decrements in performance or in normal physical
activity may not happen at these concentrations [18].
Thus, it should be noted not only that CO2 levels in poorly ventilated spaces can be found
even higher than this range of 3-4%, but also that humans may be chronically exposed to
intermittent, not continuous CO2 inhalation, a condition that by inducing mildly increased
endogenous CO2 may cause pathological adaptations. In fact, studies show that because of the
greater concentration of buffer base, acclimatization to CO2 results in desensitization of
dyspnea and in changes of set point for central respiratory controllers such that, on return to
“outdoor” air breathing, ventilation may decline below control values even in individuals
intermittently exposed to CO2 increase for 13 hours per day [15,19]. Furthermore, chronic
exposure to intermittent, mild ambient CO2 increase results also in changes of set point for
central feeding controllers which may lead to obesity. In fact, it has been shown that during
chronic inhalation of CO2 at 1.5% inspired concentration for more than one month, food
intake decreases significantly, by ~30%, but body weight does not change [17]. On return to
“normal” air breathing, food intake rises and body weight is gained [20]. Actually, stress is a
well known inducing factor of both transient and chronic loss of appetite or overeating [21].
A major causal role for CO2 has been identified with exposure of macrophages to normal
Donatella Zappulla, M.D.
4
(5%) CO2, the concentration present in alveolar space and plasma (1.2mM, PCO2 40 Torr), up
to mild (≤9%) CO2, enhancing in a rapid, reversible, and dose-dependent manner, the nuclear
factor (NF)-κB-dependent expression of tumor necrosis factor-α (TNF-α), and interleukin-6
(IL-6) [22], the pro-inflammatory cytokines which, by activating the hormonal stress response
[23], modulate food intake [21].
Inhaled CO2 induces the same physiological effects as does metabolically produced CO2,
the key chemical messenger gas in the linking of respiration, systemic circulation, and local
vascular response, to body’metabolic demands both at rest and exercise [18]. Increased CO2
needs to be removed as quickly as possible because its lowering of blood pH can denature
enzymes. A major portion of the physicochemical defenses of neutrality by the buffer systems
of the whole body takes place in muscle and bone [24]. Protein from muscle can be released
to bind with acids in the blood. This can contribute to LBM loss. Calcium and phosphorus in
bones can bind to acidic substances to neutralize them, thereby contributing to bone mineral
loss. Suggestively, greater CO2 stores matching reduced bone mineralization characterizes
Osteoporosis, a major public health problem whose risks for osteopenia, and non-spine
fractures have been shown to be significantly higher for people with higher percentage of
body fat [25]. Increased CO2 storage is present also in obstructive sleep apnea (OSA), a
prevalent disorder characterized by gradual PaCO2 elevations, associated with major nocturnal
hemoglobin desaturation, higher HbO2 affinity, and repetitive episodes of partial or complete
upper airway obstruction [26]. Most individuals with OSA have metabolic syndrome (MetS),
a common, condition consisting of a constellation of metabolic risk factors for atherosclerosis
and cardiovascular disease (ACVD) associated with abdominal obesity, namely, increased
plasma glucose values, higher blood pressure levels, higher triglycerides levels, and lower
high-density lipoprotein cholesterol (HDL-C) levels [27]. The MetS presents abnormal
intracellular ion profile in RBCs, and sustained cortisol levels [28,29] as does exposure to
CO2 at 1.5% inspired concentrations for more than one month [17,30]. Both oxidative stress
and higher levels of pro-inflammatory markers have been shown to link current air pollution
trends or excess food intake to MetS[31,32], through mechanisms similar to those operational
in OSA (i.e. higher HbO2 affinity) [23]. Individuals may be exposed to moderately increased
endogenous CO2 inhaled with ambient air pollutants, or produced as a result of the chronic
lactate accumulation due to the higher HbO2 affinity following exposure to air pollution
[23,33], or formed in nutrients’ aerobic metabolism [23,34].
Occupational epidemiological studies have provided a large body of consistent evidence
showing that the prevalence of MetS-related ACVD risk factors is higher in “active duty”
professional drivers, firefighters, and urban police workers, than in employees who work
indoor [35,36,37,38,39,40,41,42,43]. The underlying mechanisms linking all these activities
to MetS may lie in intermittent exposure to air pollution ranging from extreme to average
levels. These findings provide further support to the direct causal role of mildly increased
endogenous CO2 which has been proposed to link environmental stresses to MetS [23].
Current increased atmospheric CO2 could, at least in theory, bears a significant impact on its
pathogenesis, and RBCs which, notably, deliver O2 and nitric oxide (NO) to the periphery,
and CO2 to the lungs, could be the major target of environmental stresses, and source of low-
grade, chronic inflammation [23], a possibility not explored yet in any extent. Given the
disease burden and health costs associated with the rising prevalence of MetS, there is no
doubt that this problem must be tackled at its roots, even adopting measures to lower CO2
emissions into the atmosphere. This review focuses on MetS and pH homeostasis, the linkage
The Stress of Global Warming on Human Health
5
between breathing and feeding via CO2 economy, to disclose the “Stress” of global warming
on human health.
CO2, ION PROFILE ABNORMALITIES IN RBCS,
AND METABOLIC SYNDROME
Rising evidence suggests that oxidative stress followed by a low grade pro-inflammatory
state leading to chronic activation of hormonal stress response, coupled with accumulation of
lipid in extra adipose tissues such as the liver and the skeletal muscle, may contribute to MetS
pathogenesis [32,44]. Insulin resistance, obesity, and hypertension all share a common
abnormal intracellular ion profile in both nucleated cells and in RBCs, which might help to
explain their clinical coexistence [28]. Specifically, it has been shown that intra-cellular pH
(pHi) in RBCs is lower and also inversely linked to both body mass index (BMI) and fasting
insulin levels in normotensive and hypertensive individuals [28]; the lower the pHi, the higher
the fasting insulin level and the greater the BMI. In addition, decreased levels of intracellular
potassium (K+) and free magnesium (Mg2+i), together with elevation in intracellular sodium
(Na+i), free calcium (Ca2+i), and free 2,3-diphosphoglycerate (2,3-DPG), match lower pHi and
relate also to a reduced GSH/GSSG ratio [45]. There is also evidence that intracellular free
zinc (Zn2+i) levels are higher in RBCs of patients with untreated essential hypertension [46].
In obese humans, BMI increases as the activity of calcium-adenosine triphosphatase (Ca-
ATPase) in RBC membrane decreases [47]. Accordingly, RBC dysfunctions suggest a
common underlying mechanism of MetS pathogenesis. In fact, Mg2+i concentrations in RBCs
fall upon oxygenation as O2 binds deoxy-hemoglobin and displaces 2,3-DPG which, in turn,
binds Mg2+i[48]. Thus, BMI, fasting insulin levels, and blood pressure levels increase as soon
as hemoglobin releases less O2 because of RBC oxidation. Notably, PaCO2 rises with higher
HbO2 saturation [49], and exposure to CO2 at 1.5% inspired concentrations results in similar
RBCs dysfunctions [17].The following describes the effects of mildly increased endogenous
CO2 on RBCs homeostasis, and the biological mechanisms underlying MetS pathogenesis.
RBCs play a key role in regulating the acid–base balance of ECF. Two major molecular
elements for this in the RBC are hemoglobin, and the AE1 isoform of the anion-exchange
transporter, referred also to as band 3. Hemoglobin, at a concentration of 7mmoles per liter of
cell water (mmol (lcell water-1), is the RBC's main hydrogen (H+) buffer [50]. AE1, expressed
with ≥106 copies per human RBC, mediates a rapid trans-membrane exchange of chloride
(Cl-) for HCO3-, thereby enhancing the mass transport of CO2 in the form of plasma HCO3-.
AE1 activity is facilitated by cytoplasmic carbonic anhydrase (CA), a zinc-dependent enzyme
that catalyzes the reversible hydration of CO2 (CO2+H2O↔HCO3-+H+). Efficient AE1
activity in the RBC is vital for lung clearance of CO2, and thus for plasma and whole-body
pH maintenance [50]. In fact, although in non-erythroid cells, major acid and base effluxes
are typically mediated via separate membrane transport proteins, such as Na+/H+ exchanger
(H+-efflux) and Cl-/HCO3- exchanger (H+-influx), in the case of RBCs the main pHi sensor
and transport effectors are included within a single type of membrane protein AE1, the Cl-
/HCO3- exchanger [50]. Any variations to the net ionization state of hemoglobin, such as
those arising from changes in oxygenation status, alter pHi via changes in Cl-i [51].
Donatella Zappulla, M.D.
6
As a rule, inhaled CO2 rapidly moves down its concentration gradient into the RBC,
where it binds hemoglobin, displaces Cl-, and deoxygenates hemoglobin [52] that, in this
conformation, reacts with circulating nitrite to form methemoglobin together with release of
superoxide (O2-) and NO. Hence, glycolysis increases, pHi drops due to increased 2,3-DPG
synthesis [53], and glycolysis falls due to the marked pH sensitivity of key enzymes [54].
Beyond that, CO2 fosters the oxidation of diverse substrates by Cu-Zn-superoxide-dismutase
(SODI) which, by oxidizing the phagocytic-nicotinamide-adenine-dinucleotide-phosphate
(NADPH)-oxidase, induces also its own peroxidation [55]. This fosters the formation of
peroxynitrite (ONOO-) which, at high level, restrains glycolysis [56] as does lower pHi [54].
Thus, it has been proposed that increased ONOO- displaces zinc from RBC’ proteins, impairs
also the activity of AE1, the Cl-/HCO3- exchanger, and furthers RBCs oxidation because, with
mild CO2 inhalation, more zinc might be needed to protect erythrocytes from intracellular
ONOO- elevations [23].
Evidence suggests that RBC dysfunctions in MetS may be related to increased ONOO-
level, since this has been shown to induce (1) deactivation of glutathione peroxidase [57], (2)
inhibition of the tyrosine phosphorylation of band 3 [56], (3) hemoglobin-binding to the
membrane [56], (4) massive methemoglobin production [56], (5) irreversible inhibition of
phosphotyrosine kinase activity and glycolysis [56], (6) Ca-ATPase inhibition [58], and (7)
KCl co-transporter activation [59]. Thus, due to lower pHi or higher ONOO- levels, glycolysis
falls, oxidation rises, glutathione levels drop, the hexose monophosphate shunt in RBCs
provides energy for detoxifying peroxides [60], HbO2 affinity rises, and O2 release falls.
Increased nitrotyrosine levels in patients with MetS have been shown to be strong and
independent predictors of ACVD. Also NADPH-oxidase-dependent production of O2- has
been shown to be greatly enhanced [61]. Studies have shown that culture of macrophages in
normal (5%)CO2, as compared to air (0,03%)CO2, enhances in dose-dependent fashion the
ONOO--induced tyrosine nitration of surfactant proteins[22]. Actually, as the reaction rate for
ONOO- generation is about 2-orders of magnitude greater than the NO scavenging by oxy-
hemoglobin and about 6-fold faster than the O2- scavenging by SOD1 [55], mildly increased
endogenous CO2 may foster ONOO- formation in RBCs. Besides, more ONOO- is formed by
cells producing O2- and NO simultaneously, such as RBCs [62], activated phagocytes,
vascular endothelial cells, and smooth muscle cells [63]. This in RBCs is expected to result in
lower cellular ATP levels [56] leading to higher cytosolic Ca+ activity, oxidation, and suicidal
death of erythrocyte (eryptosis) [64] with phosphatidylserine exposure at the erythrocyte
surface, and subsequent binding to phosphatidylserine receptors at macrophages and liver
Kupffer cells from which are engulfed and degraded [65]. Locally, these phagocytic cells
produce O2- which, by activating NF-κB and JNK, generate TNF-α and IL-6 [66].
As soon as these pro-inflammatory cytokines are released into the systemic circulation,
the hypothalamic-pituitary-adrenal (HPA)-axis is activated and glucocorticoid, the end
product of the HPA-axis, restrains their production and inhibits their effects on their target
tissues [44].
The Stress of Global Warming on Human Health
7
RBC = red blood cell; oxy-Hb = oxygenated hemoglobin; SOD 1 = copper/zinc superoxide dismutase;
ONOO- = peroxynitrite; TNF-α = Tumour Necrosis Factor-α; IL-6 = Interleukin-6; NF-κB =
Nuclear Factor-κB; TG = triglycerides; HDL-C = High density lipoprotein- cholesterol; PaCO2 =
CO2 partial pressure.
Figure 1. Mechanism whereby Environmental CO2, by triggering Eryptosis, would contribute to the
development of Metabolic Syndrome.
Notable exception is the IL-6 effect on the production of C-reactive protein (CRP) and
acute-phase reactants by the liver, which is strengthened by these hormones. However, also
catecholamines, the other end products of the stress system, regulate inflammation through
stimulation of IL-6 which then inhibits TNF-α, stimulates glucocorticoids release, and
promotes the acute-phase response [44]. Compelling evidence suggests that sustained, and
disproportionate cortisol secretion induces both the abdominal fat accumulation and the
Donatella Zappulla, M.D.
8
metabolic abnormalities of MetS [29], also characterized by increased HbO2 affinity, gradual
PaCO2 elevations, and lower blood O2 supply. Failure of glucocorticoids to limit inflammatory
and neuroendocrine responses to challenges may result in the elevated levels of CRP, TNF-α
and IL-6 observed in MetS [23,65].
CO2: THE “STRESS” RULER?
Although the body requires O2 for maximizing the efficiency of metabolic processes, low
O2 levels normally do not stimulate breathing. Rather, breathing is stimulated by higher CO2
levels. Normally, the CO2 presents in human blood and alveolar gas, is constantly being
formed within cells by the aerobic metabolism of nutrients.
Basically, CO2 is transported by the blood from the cells that produce it, to the lungs,
where it is normally exhaled at the same rate at which it is produced, so long as the CO2
tension in the alveolar milieu is lower than in blood. In fact, this gas is ~20 times more
soluble than O2 in body fluids and, by moving down its concentration gradient, CO2 diffuses
from body tissues to blood, and then to air. Blood, for each 100ml of fluid, on average holds
49ml of CO2 [67], while the hydration shell of bone keeps stored in solution in its thin layer
of permanently absorbed water, 80% of body CO3-2 [68] which, by being in steady exchange
with HCO3- in ECF, is available as a fail-safe reservoir which buffers protons within narrow
physiological limits [69]. At rest, of the ~49ml of CO2 in each dl of arterial blood, 43.8ml are
in HCO3-, 2.6ml are in carbamino compounds, and 2.6ml are dissolved [67]. With food
intake, physical activity, or as soon as CO2 is inhaled at concentrations higher than 0.03% by
volume of air, blood pH declines, carbamate does not contribute to CO2 exchange [70], and
PaCO2 rises. Then, as CO2 rapidly diffuses across the blood brain barrier (BBB), is sensed by
the central respiratory chemoreceptors, and determines the need for alveolar ventilation to
normalize/oppose pH changes [71]. As a result, CO2 is blown off, PaCO2 falls, carbamate
formation raises drastically, HCO3- in ECF rises [70], and the breathing rate slows down
because even in the presence of a progressive fall in end-tidal O2 partial pressure (PO2) to
~40mmHg, hypoxia does not trigger catecholamines-driven ventilation so long as the end-
tidal PCO2 is ~ ≤40 mmHg, which is the peripheral-chemoreceptors threshold [72].
In humans, physiological CO2 sensing has also been identified in kidney, airways, and
tongue cells. CO2 sensors trigger downstream responses leading also to olfactory signaling,
taste sensation and cardiorespiratory control. CO2 may be detected by a sensor coupled to
carbonic anhydrases [73]. Responses to CO2 enhance the expression of stress hormones [20]
which also regulate gene transcription [74]. Therefore, acute changes in neuronal activity may
lead indirectly to the CO2-induced effects on the transcription of genes which may produce
pathophysiological states on greatly prolonged CO2 exposure. However, as already said, acute
shifts in CO2 levels control gene expression also by affecting directly the signaling of NF-κB
[22]. Actually, this master ruler of genes involved in immunity and inflammation [22] is
subjected to a potent counter-regulation by Ikaros, a zinc-finger protein known to activate the
hypothalamic pro-opiomelanocortin (POMC) neuronal system [75] expressing, among others,
α-melanocyte–stimulating hormone (α-MSH) which, through its action on melanocortin MC4
receptors, inhibits feeding [76]. Beyond that, Ikaros in anterior pituitary gland affects ACTH
release which, by fostering glucocorticoid release, enhances the expression of neuropeptide Y
The Stress of Global Warming on Human Health
9
(NPY), a feeding inducer [75,76]. Since Ikaros may work as a mediator of both immune and
neuroendocrine stress responses, researchers have theorized that its low expression may result
in the lower metabolic rate and chronically increased appetite leading to MetS [75].
As stated, CO2 acclimatization to chronic exposure to CO2 at 1.5% inspired concentration
results in greater concentrations of buffer base, with the consequent reduction of minute
volume ventilation, forced vital capacity, and PaO2 [15]. Beyond that, food intake rises, and
body weight is gained, on return to “normal” air breathing [20], as compared to exposure to
moderately increased ambient CO2 in which lower (~30%) food intake, without body weight
changes, matches increased ventilation [17]. Accordingly, adaptations to chronic exposure to
intermittent, mildly increased ambient CO2 may result in lower O2 uptake, reduced metabolic
rate, and excess feeding, as it occurs in MetS. Food intake may rise because mildly increased
endogenous CO2 enhances the expression of TNF-α and IL-6, which further glucocorticoids
release, with consequent higher expression of the oroxigenic NPY. Hence, CO2 does not only
determine the need for alveolar ventilation, but it is also the “stress” ruler of both transient
and chronic overeating or loss of appetite [21], to normalize/oppose pH changes.
PH HOMEOSTASIS, THE LINKAGE BETWEEN BREATHING
AND FEEDING VIA CO2 ECONOMY
It is well established that food ingestion has an impact on respiratory functions. Basically,
feeding raises blood CO2 levels and, according to the respiratory quotient (RQ) which
expresses the making of CO2 from the amount of O2 utilized to metabolize each specific
substrate, 747ml of CO2 are produced from the oxidation of 1gr of carbohydrate (CHO: RQ =
1; 1gr glucose +747ml O2 → 747ml CO2 + 0.60gr H2O); 848 ml of CO2 are produced from
the oxidation of 1gr of protein (RQ = 0.8; 1gr protein + 992ml O2→ 848ml CO2 + 0.38gr
H2O); and 1.416 liters of CO2 are produced from the oxidation of 1gr of fat (RQ = 0.7; 1gr
tripalmitin + 2.011 liters O2→ 1.416 liters of CO2 + 1.09gr H2O) [34]. Thus, O2 supply plays
a key role in the selection of the fuel more suitable to grant CO2, and control ventilation,
according to pH homeostasis.
Studies have shown that plasma glucose tissue uptake and muscle glycogen oxidation
raise maximally with growing exercise intensity [77], as only anaerobic glycolysis grants the
CO2 which furthers ventilation and O2 uptake [67]. In contrast, peripheral lipolysis rises with
exercise intensity up to ~55-65% of VO2 max, but declines at higher intensity [77], because
only glycogen and/or amino acid-derived glucose can be oxidized with reduced O2 supply.
Further researches have shown that both minute ventilation and ventilation in response to
hypoxia and hypercapnia increase after a meal containing CHO or protein [78,79], whose
metabolism produces more CO2, as compared to fat which needs more O2 to be oxidized [34].
Indeed, lower rates of fat oxidation (R.Q = ≥ 0.7, that is, reduced CO2 production due to
lower O2 availability) have been shown to predict weight gain [80,81]. This likely occurs
because fat gain implies LBM loss, and phosphates wasting implies higher HbO2 affinity and
lower O2 supply [53]. Because with food intake increased endogenous CO2 levels further
ventilation, it may be presumed that the excess feeding leading to weight gain is simply a way
to raise O2 uptake. Indeed, the main task of brainstem networks is pH homeostasis, regardless
of the body’s metabolic demands. Thus, CO2 economy links breathing and feeding.
Donatella Zappulla, M.D.
10
Table 1
H2O = WATER; RQ = RESPIRATORY QUOTIENT.
Accumulating evidence show that neurotransmitters such as noradrenaline, dopamine,
and serotonin, and corticotropin-releasing hormone (CRH), the key hypothalamic regulator of
the HPA axis, are involved in the control of ventilation [74], as well as in stress responses that
include behavioral changes such as bulimia or anorexia [21].
In essence, both feeding and breathing pattern depend on on the same nerve transmission
mediated by monoamines which varies according to PaCO2 because aromatic monoamines
cannot passively diffuse across the blood brain barrier (BBB).
As a rule, when increased CO2 alters pH, brain cells synthesize the monoamine species
from the amino acid precursors which have been actively transported through the BBB at that
moment [82]. Notably, with CHO loading, increased levels of insulin favor the entry of the
amino acid tryptophan (TRP) into brain cells, whereas other neutral amino acids cannot reach
the level needed to form catecholamines [82]. TRP level elevations foster the production of
serotonin (5HT) which, within the central nervous system, function as inhibitory mediators of
feeding [83], and breathing [84].
In contrast, with protein loading, most amino acids do not sustain insulin release. Thus,
brain catecholamines levels rise, plasma concentrations of their amino acid precursors fall,
and lower levels of blood dopamine(DA) prevent carotid body-mediated DA inhibition of
ventilation [84]. As increased O2 uptake sustains fat oxidation[34], catecholamines promote
lipolysis, and this results in higher plasma levels of free (non-esterified) fatty acids (FFA)
which compete with TRP for binding albumin [85]. As a result, free TRP levels increase.
But with hyperventilation, respiratory water loss may exceed the metabolic production of
water, and hypothalamic vasopressin (AVP) release is involved as increased PCO2 promotes it
[86]. Hence, AVP depresses the slope of the ventilatory response to CO2 through stimulation
of AVP V1-receptor [86], and decreases the carotid body response to hypoxia through the
disinhibition of a stretch-inactivated cation channel [87].
Later, as free TRP levels increase, and blood glucose levels rise due to catecholamines-
induced muscle glycogenolysis, insulin favors 5HT production which then slows down
ventilation until blood glucose level falls, brain 5HT decreases, and higher catecholamines
level furthers breathing and feeding [83,84].
The Stress of Global Warming on Human Health
11
Table 2-
R.Q = RESPIRATORY QUOTIENT; FFA = Free Fatty Acid.
Significantly, however, zinc status per se, rather than brain concentrations of tyrosine or
TRP, appears to influence both feeding and breathing [88,89]. Zinc deficit, which has been
shown to occur across a wide range of population groups [90], may cause loss of function of
zinc-finger proteins [91] such as Ikaros, thereby affecting ACTH release [75]. This may result
in longer tissue exposure to glucocorticoids, maximizing their catabolic, lipogenic effect [92].
With this in mind, the linkage between breathing and feeding via CO2 economy is now
evident.
INCREASED ENDOGENOUS CO2: THE “STRESS”
OF GLOBAL WARMING ON HUMAN HEALTH
Hypothalamic orexin/hypocretin neurons have emerged as key orchestrators of several
physiological functions such as normal stimulation of breathing, exploratory responses to
food shortage and feeding. It has been shown that CO2 powerfully triggers the firing of orexin
cells through mechanisms involving acid-induced inhibition of postsynaptic leak-like K+
channels [93]. Cells containing these peptide transmitters respond to CO2 according to the
ambient fluctuations in the concentration of nutrients and appetite-regulating hormones [93].
Centrally administered orexin affects NF-κB signaling as does CO2. In fact, orexin activates
neurons in paraventricular nuclei, CRH/AVP, ACTH release, and raises the plasma level of
glucocorticoids [94]. These exert their effects through ubiquitously distributed zinc-finger
receptors which control transcription factors such as NF-κB [95,96], thereby modulating
TNF-α and IL-6 expression.
Actually, the stress response do not only elicit inflammation in order to protect organisms
against stress, but also repairs tissue injuries and alert the immune system from jeopardizing
cellular damage. With moderately increased endogenous CO2, as soon as RBCs oxidation
threatens pH homeostasis, TNF-α may induce the coincident appearance of MetS ACVD risk
factors [97] to restore the lost balance. In essence, TNF-α inhibits auto-phosphorylation of
tyrosine residues of insulin receptors and promotes serine phosphorylation of insulin receptor
substrate-1; this, in turn, triggers serine phosphorylation of insulin receptors in adipocytes,
prevents the normal tyrosine phosphorylation, and interferes with transduction of the insulin
Donatella Zappulla, M.D.
12
signal. Hence, insulin resistance results in Akt (protein-kinase-B) inhibition and subsequent
inhibition of NO-synthase (NOS) [97]. Reduced NO bioavailability may impair endothelium-
mediated vasodilatation and raise blood pressure, but it favors anaerobic glycolysis. Besides,
due to insulin resistance, adipocyte hormone-sensitive lipase activity is poorly suppressed and
there is further enhancement of lipolysis with higher triglyceride levels resulting in lower
HDL-C levels [97]. Higher FFA levels favor the production of 5HT which, by slowing down
ventilation, prevents hemoglobin oxidation on oxygenation. Accordingly, TNF-α promotes
adaptations such as insulin resistance-hyperglycemia, NOS inhibition, reoccurrence of
glycolysis, and decreased O2 uptake whose joined effects overall reduce RBCs oxidation and
maintain blood O2 release. Inflammation is, indeed, a fundamental survival mechanism but it
is dangerous when its transient, physiological adaptations are converted to a long-lasting,
pathological state. Potential causes for steady CRH activation and glucocorticoids release
include environmental stresses, which as explained, result in higher HbO2 affinity and mildly
increased endogenous CO2 [23]. Ominously, as atmospheric CO2 increases, Global Warming
may threaten human health. Thus, the following reviews the mechanism through which
intermittent exposure to mildly increased ambient CO2 may lead to MetS and/or osteoporosis.
The acute sequels of exposure to a raised ambient CO2 concentration have been well
established [17]. RBCs pHi falls, glycolysis inhibition furthers RBCs oxidation, HbO2 affinity
rises, and elevations in minute ventilation of ~1l min-1-2 occur as the end-tidal PO2 drops, and
the hypoxic drive senses increased PaCO2 and triggers hyperventilation [15,19,20]. In essence,
CO2 deoxygenates hemoglobin, eryptosis fosters phagocytic cells to release TNF-α and IL6,
and the hormonal stress response promotes adaptations whose joined effects overall lower
RBCs oxidation and preserve blood O2 supply. Normally, CRH neurons activation causes
anorexia, and glucocorticoids induce overeating by fostering NPY and/or orexin expression,
and suppressing both CRH and locus ceruleus/NA-sympathetic systems [92]. NPY activates
also the parasympathetic system which helps with digestion and storage of nutrients [98,99],
whereas inhibitory feedbacks of glucocorticoids receptors on NF-κB signaling lowers ACTH
secretory response, and feeding [92]. However, during CO2 inhalation, catecholamines trigger
vasoconstriction, induce muscle glycogen wasting and, by fostering ventilation, further
dehydration. Thus, AVP is released, and blood glucose levels rise also through the effects of
AVP on liver glycogenolysis. Both ventilation and aerobic metabolism decrease [86,100] also
because with higher blood glucose levels insulin favors 5HT actions and lipogenesis. Besides,
glucocorticoids activate the renin-angiotensin-aldosterone system which averts further body
water depletion [101]. As a result, during exposure to CO2 at 1.5% inspired concentration for
more than one month, also food intake decreases, whereas an increased number of adipocytes
releases TNF-α and IL-6 which may promote the coincident appearance of ACVD risk factors
to restore pH balance.
Due to higher HbO2 affinity body fat may increase because fat oxidation requires more
O2 than the oxidation of either protein or CHO [34]. Hence, lower fat oxidation may lead to
fat accumulation in the chest wall and abdomen which, by reducing the compliance of the
respiratory system [102], decreases forced vital capacity [15]. This might help to reduce the
oxidation of deoxygenated hemoglobin on oxygenation. Beyond that, an increased number of
adipocytes release leptin [103] which prevents respiratory depression [104], inhibits bone
formation [105], and decreases appetite by suppressing NPY and/or orexin, and supporting α-
MSH [21], through a hypothalamic relay, as impending dehydration might serve to shorten a
period of feeding, or prevent feeding [106].
The Stress of Global Warming on Human Health
13
Overall, during exposure to mildly raised ambient CO2 levels, slow adaptive processes in
electrolyte exchange and pH regulation results in higher PaCO2 due to reduction in forced vital
capacity. Presumably, food intake decreases much to reduce PaCO2, and body weight does not
change [17] due to the water retention required to hydrate and store the inhaled CO2 as ECF
HCO3-, and as bone CO3-2. Basically, with CO2 acclimatization, compensatory processes for
respiratory acidosis result in metabolic alkalosis [107] which, on return to “normal” air
breathing, constantly triggers glucocorticoids release. In fact, with abdominal accumulation, a
lower compliance of the respiratory system causes the decline of forced vital capacity, minute
volume ventilation, and PaO2 [15], with ensuing chronic lactate accumulation. This, by raising
HbO2 affinity, results in higher PaCO2[49], and RBCs oxidation with TNF-α and IL-6 release
from phagocytic cells. Besides, the relentless LBM loss coupled to the body fat gain arisen
during exposure to CO2 implies not only that HbO2 affinity rises, and O2 release falls because
the loss of body phosphate impairs 2-3DPG synthesis [53], but also that adipocytes release
TNF-α and IL-6. Presumably, on return to normal air breathing, food intake rises, and insulin
resistance persists until an ampler number of adipocytes release enough leptin which lowers
bone formation and food intake without respiratory depression. In few words, with chronic
exposure to intermittent, mildly increased CO2, body buffers loss sets a vicious cycle in which
the more CO2 is inhaled and stored, the more food is eaten to raise PaCO2, foster ventilation,
and save pH homeostasis.
With time, however, steady activation of the stress response leads to the loss of bone and
muscle which, due to parallel abdominal fat accumulation, causes shallow, rapid breathing
(not conscious tachypnea), turns up the set point for central feeding controllers, and induces
overeating with its chronic pathological consequences, namely, MetS and osteoporosis.
CONCLUSION
Chronic exposure to CO2 at 0.5-3% inspired concentrations alters pH homeostasis and
fosters body CO2 storage in humans [15,16, 17], as does increased atmospheric CO2 in the
terrestrial biosphere. Increased CO2 stores in bone are present in osteoporosis, whose risks for
osteopenia, and non-spine fractures have been shown to be significantly higher for subjects
with higher percentage body fat, independent of body weight [25]. Fat accumulation and
increased CO2 stores characterize also MetS which, despite lifestyle changes and the use of
pharmacologic approaches to lower plasma cholesterol levels, continues to be, and it is
expected to become the major cause of disability and death in the world by 2020 [108].
Intriguingly, prevalence of MetS-ACVD risk factors is reportedly higher in occupational
activities implying lasting variations in exposure to air pollutants, than in general population
[35,36,37,38,39,40,41,42,43]. Thus, it has been proposed that mildly increased endogenous
CO2 inhaled with ambient air pollutants, or produced as a result of the lactate accumulation
due to the increased HbO2 affinity following exposure to air pollution [23,33], or formed in
nutrients’ aerobic metabolism [23,34] links environmental stresses to MetS pathogenesis [23].
In fact, CO2 triggers RBCs oxidation and eryptosis, with phosphatidylserine (PS) exposure at
erythrocyte surface, and consequent binding to PS receptors at phagocytic cells that, once
activated, release TNF-α and IL-6, the pro-inflammatory cytokines related to stress response
and MetS pathogenesis.
Donatella Zappulla, M.D.
14
HPA = Hypothalamic-Pituitary-Adrenal; FFA = Free Fatty Acid; ACVD = Atherosclerotic-
Cardiovascular Disease.
Figure 2. Mechanism whereby chronic exposure to intermittent, mildly increased ambient CO2 would
further food intake and contribute to the development of ACVD risk factors , Metabolic Syndrome, and
increased Osteoporosis risks for osteopenia, and non-spine fractures.
Consistent with this hypothesis, it has been reported that exposure of macrophages to 5-
up≤9% CO2, as compared to elevated (≥9-12.5%) CO2, results in enhanced expression of
TNF-α and IL-6 [22]. Culture of macrophages in normal CO2, as compared to in air CO2, has
been shown to enhance the tyrosine nitration of surfactant proteins induced by ONOO-[22]
which, at high levels, fosters eryptosis. Clinical studies have shown significantly higher
translocation of phosphatidylserine to the outer plasma membrane leaflet in RBCs from
patients with MetS than in age-matched healthy controls [109]. Increased eryptosis has been
The Stress of Global Warming on Human Health
15
observed also in patients with type II diabetes [110,111], in specimens from nonalcoholic
steato-hepatitis patients, and in animal models of non-alcoholic fatty liver disease [112], all
conditions related to MetS [65]. So far, it seems undeniable that pH homeostasis, the linkage
between breathing and feeding via CO2 economy, discloses the stress of Global Warming on
human health. This is potentially a very rewarding area for research.
Statement on potential conflict of interest: The author does not have any financial or
proprietary interest in the subject matter discussed in this manuscript. The author has not
received any funding or financial support through sponsorship, grants, consultancies,
honoraria, patent ownership or other. Furthermore, there is no funding and extra funding
received for academic research of this work.
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