Hypoxia physiology and everything included

Hypoxia

1. Hypoxia
1.Definition and classification
2.Indicators of oxygen homeostasis.
3.Characteristics of different types of hypoxia.
4.Adaptation to hypoxia: main mechanisms.
5.Cellular and body dysfunctions during hypoxia.

2. Respiration
consists of several processes:
1.О2 andСО2 exchange between external
environment and alveoli (alveolar
ventilation)
2.О2 andСО2 exchange between alveoli
and blood (diffusion)
3.Transport of gases in blood
4.О2 utilization in tissues and СО2
formation (cellular respiration)

3. Indicators of oxygen homeostasis
Indicators(blood) Normal
a –arterial blood
v –venous blood
1. Partial pressure of О
2 (oxygentension) р
aО
2=80-100 mm Hg
р
vО
2=35-45 mm Hg
2. О
2concentration (oxygencontent) С
aО
2 = 16,5-20,5%
С
vО
2 =12-15%
3. ArteriovenousО
2 gradient(АVG) С
aО
2 -С
vО
2
=5-7 %
4. Coefficient of oxygen utilization АVG/С
aО
2 = 0,25-0,4*
5. Oxygen saturation S
аО
2= 96-98 %
S
vО
2= 60 %
*Oxygen utilization coefficientХ 100% = 25-40%, it means that tissues can utilize about 25-
40% О
2from the arterial blood

4. Hypoxia
This is a typical pathological process that develops as a result
of an inadequate supply of O2 to tissues or its incomplete
utilization.
It is characterized by insufficient biological oxidation and
energy deficiency.
•Hypo
•Oxygenium
(Greek) -oxygen
•Hypo
•Oxydation
Nota bene!There is no real O2 deficiency in the body at some
types of hypoxia!!!For example, it includes the hemic,
tissue hypoxia, and also the forms of circulatory hypoxia in
which blood oxygenation in the lung is not impaired
Etymology:

5. Types of hypoxia
By duration:
fulminant
acute
subacute
chronic
By severity:
mild
moderate
heavy
critical (fatal)
By prevalence :
Local
General
By etiology:
exogenic(hypoxic hypoxia)
respiratory
cirxulatory
hemic
tissue (hystotoxic)
mixed

6. Main processes of respiration and types of hypoxia
(etiological classification)
Respiratory system
Blood oxygenation
О
2transport in
blood
Circulatory system
Blood (erythron)
О
2utilization in
tissues
External О
2
(pО
2)
Cellular respiration
Exogenous hypoxia
Respiratory hypoxia
Circulatory hypoxia
Hemic hypoxia
Tissue hypoxia
Mixed hypoxia

7. The partial pressure of any gas in a gas mixture (air) is
proportional to its concentrationand the level of
atmospheric pressure
Exogenous hypoxia
Normobaric Hypobaric

8. Exogenous normobaric hypoxia
It is caused by a decrease in O2
concentration in the inhaled air at normal
(or even elevated) atmospheric pressure
Обрушение домов, завалы
Accidents in mines
Submarine accidents, disruption of air flow
into divers' suits, etc.

9. Exogenous hypobaric hypoxia
Mountain sickness (climbing to
high altitude without oxygen
supply)
Decapsulationof aircrafts,
hot air balloon flight to high altitudes, etc.
It is caused by a decrease in atmospheric
pressureat a normal concentration of O2
in the air

10. Indicators of oxygen homeostasis at
exogenous hypoxia
•The main indicator-↓p
aО
2(arterial hypoxemia)
Other indicators:
•↓ p
vО
2
•↓С
aО
2and↓ С
vО
2
•↓ S
aО
2and↓ S
vО
2
•↓ p
аСО
2 (hypocapnia)
•↑ рН (respiratoryalkalosis)
Hypoxia Hyperventilation
General cyanosis

11. Changes in blood gases tension at exogenous hypoxia
(in dependence on the altitude)
Altitude Аtm. Р (mmHg)РаО2(mmHg)РаСО2(mmHg)
Sea level 760 100 40
3510 м (La Pas)495 60 30
6400 m 344 38.1 20.7
7440 m 300 33.7 15.8
7830 m 288 32.8 14.3
8848 m
(Everest)
253 29.5 7.5

12. Respiratory hypoxia
The main indicator-↓p
aО
2
(arterial hypoxemia)
Other indicators:
•↓p
vО
2
•↓С
aО
2
and↓ С
vО
2
•↓S
aО
2
and↓S
vО
2
But!
•↑p
аСО
2 (hypercapnia) and
•↓рН (gas acidosis)
Etiology is the impairment of:
1.Alveolar ventilation
(pathology of airway, lung,
chest, impaired regulation of
respiration).
2.Diffusionof gases in the
lungs.
3.Lung perfusion(impaired
pulmonary blood flow)
This is similar
to exogenous
hypoxia!
General
cyanosis

13. Circulatory hypoxia
↓ cardiac
output
Decreased
venous blood
return to the
heart
1. Heart diseases
2. Dysregulation of
vascular tone Collapse
Decreased pumping
function of the heart
3. Blood loss, loss of
plasma (plasmorrhea)
Hypovolemia
4. Hypohydration
Etiology–
impaired blood
circulation

14. Circulatory hypoxia, due to a decrease in cardiac output,
decreased vascular tone or hypovolemia, leads to the decrease
in tissue blood flow, i.e. cells receive less O2 per time
•There is general and local circulatory hypoxia
•Local hypoxia is characteristic of ischemia, venous hyperemia, and stasis
Ischemia

15. Circulatory hypoxia
Показатели:
•p
aО
2–normal, ↓p
vО
2
•С
aО
2–normal,
, ↓ С
vО
2
•S
aО
2–normal,↓S
vО
2
↑ coefficient of oxygen
utilization
↑arterial-venous О2
gradientAcrocyanosis at
circulatory hypoxia
↓ cardiac
output
Collapse
The main features of
circulatory hypoxia :
Decreased blood flow velocity in
tissues
Enhanced utilization ofО2 by tissues
Nota bene!It can only partially
compensate tissue О2deficit,
but does not eliminate it!!
↓ blood
volume

16. Hemic hypoxia
Types:
1. Anemic(↓ erythrocytes
andHbin blood)
2. Toxic(Hb forms, poorly
binding О2)
↓ О
2concentration (content)in
blood(↓ C
аO
2 и ↓ C
vO
2 )
Decreased oxygen binding
capacity
Anemia Normal
The main features of HH:
Pallor in hemic hypoxia

17. О
2concentration in the blood (%)0
2
4
6
8
10
12
14
16
18
20
Растворенный Связанный с Hb
~0,3 %
~19 %
Arterial blood
Oxygen is transported in the blood in two ways:
•Dissolvedin the blood (1.5%),
•Bound tohaemoglobin (98.5%).
Nota bene!paO2in the blood is due to its dissolved part
Dissolved Bound to
haemoglobin

18. О
2concentration in blood (and oxygen binding capacity)
•Only 0,2 mlof О
2is dissolved in 100 ml of blood at p
aO2 = 95 mm Hg
since oxygen has such a low solubility
•O
2in the blood is mainly associated with hemoglobin (oxyhemoglobin,
HbO
2)
•1 g of Hb binds 1.34 ml of О
2(Hüfner's constant)
•Normal amount of Hb = 135-155 g / l (in 100 ml -13.5-15.5 g)
•Thus, 100 ml of blood can transfer about 17.4-20.5 ml of O
2in the form of
HbO2
•+ 0,3 мл О
2dissolved in plasma
•Since normal Sa O
2is 96-98%, the oxygen binding capacity of the blood is
approximately = 16.5-20.5 % (this means that 100 ml of blood can bind
about 16.5-20.5 ml of O2)
Oxygen binding capacityis the maximum amount of O2 that can be
bound by 100 ml of blood
It is calculated according to the formula:
O2 binding capacity = (1.34 mL O2/g Hb) ×(g Hb/100 mL blood)

19. Hemoglobin

20. Human hemoglobins
Hb A is absolutely predominant form of Hb in adults
Hb F binds O2 with higher affinity than Hb A
Hb F is predominant in the fetus and newborns blood (50-80%)
Hb A almost completely replaces it during several months after birth

21. Indicators:
Anemic form:
•p
aО
2–normal!
•p
vО
2 –normal or↓
•С
aО
2andС
vО
2↓
•S
aО
2andS
vО
2 –
normal
•AVGmay be ↑
(hypoxia compensation
due to↑ utilization ofО
2)
Toxic form:
•p
aО
2–normal!
•p
vО
2 –normal or↑
•С
aО
2andС
vО
2↓
•S
aО
2andS
vО
2 ↓
•Under the action of toxic
substances, there may be a
simultaneous inhibition of
the enzymes of the
respiratory chain -therefore
AVG may be ↓
But!

22. Carbon monoxide poisoning(СО)
СО
•The affinity of Hb for CO is 300 times higher
than that of O2
•Carboxyhemoglobin has a cherry red hue →
this is a characteristic skin color in case of CO
poisoning

23. Methemoglobin
Etiologic factors are the oxidants (nitrates, nitrites, endogenous peroxides, etc.)
•An excess amount of metHb can be formed by the action of some drugs
(sulfonamides, amidopyrine, etc.)
•Methemoglobin reductase catalyzes the reverse reaction.
•Methemoglobin is a form of
Hb in which Fe2+ is
converted to Fe3+
•In this form, Hb does not
bind O2.
•The blood turns brown
("chocolate blood")

24. Hereditary methemoglobinemia is due to
methemoglobin reductase deficiency
Habitus of patient suffered from hereditary methemoglobinemia
→

25. Tissue (hystotoxic) hypoxia
It is associated with impaired oxygen utilization during tissue respiration
Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from
NADH or FADH
2to O
2by a series of electron carriers.oxidative phosphorylation generates 26 of the 30
molecules of ATP that are formed when glucose is completely oxidized to CO
2and H
2O

26. Mytochondrion
Sustrates(glucose,
ВЖК и др.)
Glucose
Electron transport chain
ATP
synthesis
Fatty
acids
Аc-СоА

27. Tissue (hystotoxic) hypoxia(main causes)
1.Mytochondrial dysfunction (damage of mitochondria ) in pathological processes
2.Impairment inthe Krebs cycle:
•decreased availability of substrates (substrates deficiency). It is characterized as substrate
hypoxia
•inhibition of the Krebs cycle enzymes by poisons (aconite, monoiodoacetate, Na fluoride, etc.)
•binding of NH3 to alpha-ketoglutaric acid in hepatic insufficiency with the formation of glutamic
acid (because the neutralization of NH3 in the liver is impaired)
3. Disorders associated with a deficiency or inhibition of respiratory chain enzymes:
-deficiency of vitamins, especially B2, PP, as well as B1, pantothenic acid, lipoic acid
-deficiency of microelements, especially Fe, Cu
-enzyme inhibition, which can be specific (cyanides bind to cytochrome oxidase, leading to its
blockade), nonspecific (binding of the SH-group of proteins by heavy Me ions, changed pH),
competitive (for example, blockade of SDH with malonate)
4. Action of uncouplers of oxidative phosphorylation:
-exogenous-2,4-dinitrophenol, anticoagulants -for example, dicumarin. These are
protonophores that facilitate the transfer of H + protons through the inner membrane of MTX
into their matrix → decrease in the proton gradient → impairment of phosphorylation → ↓ ATP
synthesis
-endogenous-acidosis, excess of fatty acids, Ca2 +, thyroid hormones

28. Krebs cycle
Mechanisms of impairments:
•Decreased availability of substrates (substrates deficiency). It is characterized
as substrate hypoxia.
•Inhibition of the Krebs cycle enzymes (for example, by malonic acid, which
structure is similar to the structure of the main substrate of this enzyme –
succinate).

29. Protonophores
Protonophores are incorporated into the inner membrane of mitochondria and promote the
leakage of H+ protons through the inner membrane into the matrix → this leads to a
decrease in the proton gradient, which is formed due to the transfer of H + protons from
the matrix to the intermembrane space (in the electron transport chain).
H+ gradient is required for the subsequent transfer of H+ back to the matrix (through the ATP
synthase), the transfer energy is used for the synthesis of ATP. When proton gradient
decreases, this mechanism is disrupted, which leads to uncoupling of oxidation and
phosphorylation → ↓ of ATP synthesis
Protonophores
Mytochondrion
Outer membrane
Inner membrane

30. Inhibitors of cellular respiration
Н
+
Н
+
Н
+

31. Показатели кислородного гомеостаза при
тканевой гипоксии
•p
aО
2is normal
•С
aО
2is normal
•S
aО
2is normal
As result of the↓ utilization ofО2 in tissues:
•p
vО
2 ↑
•С
vО
2↑
•S
vО
2↑ (arterialization of the venous blood)
Main indicators:
•↓coefficient of О
2utilization
•and↓AVG of O
2
Due to arterialization of the venous blood, there is no cyanosis!

32. Mixed hypoxia
1. It occurs when one factor simultaneously impairs several of homeostasic
mechanisms (for example, a blood loss leads to the circulatory and hemic
hypoxia, barbiturates inhibit both cellular respiration and respiratory center
in CNS
2. Another variant occurs when different types of hypoxia develop they develop
sequentially (one by one). For example:
↓cardiac output
Circulatory hypoxia
Congestion of blood in the pulmonary
circulation (venous hyperemia of the lung)
Left ventricular failure
Pulmonary edema
Respiratory hypoxia

33. Self-study questions
Explain the terms:
•Substrate hypoxia
•Overload hypoxia
•Hyperoxic hypoxia
-What types of hypoxia (one or more) are they based on?
-Explain their mechanisms.

34. Adaptation to hypoxia: the main mechanisms
Physiological systems involved in
the adaptation to hypoxia:
•External respiration system
•Cardiovascular system
•Blood
•Tissue respiration
Adaptation also involves the
nervous and endocrine
systems
•Immediate mechanisms
•Long-term mechanisms
There are two strategies:
•«Combat for oxygen» -
activation of systems contributing
to the entry of O2 into the body,
its transport and utilization
•Adaptation to the reduced level
of O2 and decreased intensity of
biological oxidation

35. Respiration
Immediate Long-term
1.Hyperventilation due to ↑ RR and ↑
depth of breathing.
Mechanisms:
-reflectory(reaction of chemoreceptorsof
the carotid sinus zone in response to ↓ О2
-direct action of H + ions (due to lactate
acidosis) on the neurons of the respiratory
center
2. Opening of unventilated alveoli.
3.Exogenous hypoxia is accompaniedby
pulmonary arterial vasospasm to maintain
the normal rate of ventilationand perfusion.
Vasoconstriction in response to low oxygen
tension (hypoxia) in pulmonary arteries is an
important physiological adaptation to
reroute blood flow to areas of higher
oxygenation for effective gaseous exchange
(see figure). But!it leads to acute
pulmonary hypertension(PH).
1.An increase in the respiratory surface
area and vital capacity.
2.Hypertrophy of the respiratory muscles.
3.Hypertrophy of the vascular smooth
muscles (but!this adaptation can lead to
chronic pulmonary hypertension, PH)

36. O2 sensors (chemoreceptors) are located in carotid bodies

38. Circulation
Immediate Long-term
1.Increase in cardiac output(CO) due to
↑ in both heart rate (HR) and stroke
volume (SV) –CO=SV* HR
2. ↑ vascular tone and arterial pressure
Mechanisms:
–reflex activating the medullar vaso-
motor center (↓ O2 tension activates
the chemoreceptorsof carotid bodies)
-activation of the sympathoadrenal
system (hypoxia is stressfulfor an
organism)
3. Increased blood flow (preferentially in
vital organs)
4. Opening of non-functioning capillaries
1.Myocardial hypertrophy.
2.Increase in the number of capillaries
due to neoangiogenesis(formation of
new vessels as a result of activation of
the vascular endothelial growth factor
VEGF synthesis ).
3.Formation of collateral vessels.

39. Blood (erythrocytes)
Immediate Long-term
1. Blood release from the depot induced
by catecholamines (activation of SAS).
2. Shift of the oxygen saturation
(dissociation) curve (for details -see
below)
1.Hyperplasia of erythroid cell line in
bone marrow → erythrocytosis
2.Shift of the oxygen saturation
(dissociation) curve
Factors affecting the affinity of haemoglobin for oxygen:
-pH/pCO2–When H+/pCO2 increases and pH decreases, Hb enters the T state and its
affinity for oxygen decreases.This is known as the Bohr effect.Inversely, when H+/pCO2
decreases and pH increases, the affinity of haemoglobin for oxygen increases.
-temperature–At increased temperatures, for example in active muscles, there is an
increase in heat production which decreases the affinity of haemoglobin for oxygen.At
decreased temperatures, for example when there is decreased tissue metabolism, there is
decreased heat production and the affinity of haemoglobin for oxygen increases.
-2,3-diphosphoglycerate (2,3-DPG)–2,3-DPG, sometimes referred to as 2,3-BPG, is a
chemical found in red blood cells from the glucose metabolic pathway. 2,3-DPG binds to the
beta chains of haemoglobin, so increased 2, 3-DPG levels results in it binding to
haemoglobin, decreasing the affinity of haemoglobin for oxygen. Inversely, when there are
decreased 2,3-DPG levels, for example when there is decreased tissue metabolism, there
are less 2,3-DPG molecules binding to haemoglobin, hence it has a higher affinity for
oxygen as there are more opportunities for it to bind.
The affinity of haemoglobin for oxygen also results in a shift in the oxyhemoglobin
dissociation curve.An increasein oxygen affinity results in the curve shifting to the left,
whereas a decreasein oxygen affinity results in the curve shifting to the right.

40. Oxygen saturation (dissociation) curve
Normal
When рН,рСО2, t°change
Oxygen saturation (dissociation) curve in alpine
animals (lama -1 and vicuña -2) adapted to
high altitude

41. Activation of erythropoiesis

42. Cellular respiration
Immediate Long-term
1. Activation of glycolysis.
Mechanisms: hypoxic -induced
hypoergosis blocks the inhibitory effect
of ATP on phosphofructokinase, one of
the key enzymes of glycolysis. As a
result, glycolysis is activated.
It is followed by the development of
lactate acidosis.
Glycolysis requires the enhanced amount
of subsrates. They can be delivered due
to increased glycogenolysis,
gluconeogenesis, lipolysis (impact of
stress hormones -catecholamines,
glucocorticoids).
2. Glucocorticoids, opioid peptides also
contribute to the oxidation and
phosphorylation coupling
Enhancing efficiency of biological
oxidation by:
-↑ the number of mitochondria.
Normally, the division of mitochondria
ensures their renewal every 10 days, in
hypoxic condition -more intensively.
-Activation of the respiration chain
enzymes synthesis as a result of
increased gene expression
-↑ oxidation and phosphorylation
coupling
-↑ glycolysis

43. Cellular oxygen sensor is hypoxia-inducible factor (HIF-1), which regulates
gene expression required for adaptation to hypoxia
In normoxia, the HIF-alpha isoform is destroyed by the ubiquitin-proteasome system. In hypoxia,
two isoforms (HIF-alpha and HIF-beta) activate a number of genes in different cells that contribute
to adaptation to hypoxia

44. Processes Genes expression
Metabolism and energy GLUT1, 3
Hexokinase
Phosphofructokinase
Lactate dehydrogenase
Pyruvate kinase, etc.
Angiogenesis Vascular endothelial growt factor
(VEGF) and
Vasomotor control Adrenomedullin
NO synthase
Alpha1-adrenoreceptor
Erhythropoiesis Erhythropoietin(kidney)
Fe metabolism Transferrin and its receptor
Ceruloplasmin
Others Heme oxygenase, carboanhydrase
HIF-1act as a transcription factor activating a number of
processes in different cells aimed for adaptation to hypoxia

45. Hypoxia
Decreased ATP synthesis
Energy deficit
Impairment of the main kinds of
cellular performance
Mechanical
(muscle
contraction)
Chemical
(protein,
DNA and
RNA
synthesis)
Electrical
(changes
in
membrane
potential)
Transport
(decreased
activity of
АТPases)
Hypoxia can lead to cell death (due to necrosis or apoptosis) ,
atrophy, dystrophy
Glycolysis ↑reactive
oxygen
species
Ацидоз
↑ lipid
peroxidation
Cellular dysfunctions induced to hypoxia

46. Resistance to hypoxia differs between the organs
Organs intensively consumed O2
(at rest):
-Myocardium
-Brain (gray matter)
-Liver
-Renal cortex
Lowest and highestresistance to
hypoxia in the nervous
system:
-Cortex (survivalonly for 2-3
min of complete anoxia)
-Cerebellar cortex
-Hippocampus
-Medulla oblongata (8-12 min)
-Spinal cord
-Peripheral NS (50-60 min)

47. Hypoxytherapy
Hypobaric
hypoxia:
«Mountain air»
equipment
Normobaric hypoxia
•It is used to train the body's ability to adapt to hypoxia
•It leads to the development of cross-adaptation to other situations
accompanied by hypoxia (for example, high physical activity), as well as
to an increasing general resistance of the body
•Resistance training in hypoxia constitutes a promising new training
strategy for strength and muscle gains

48. Oxygen therapy
Hyperbaric oxygen
therapy
Oxygen therapyis used in conditions accompanied by
the development of hypoxia (for example,
respiratory failure with COVID-19)
Hyperbaric oxygen therapyincreases the amount of
the dissolved O2 in the blood plasma.
It may be used in the treatment of:
•Some infections, including drug resistant forms
•Sores and gangrene that will not heal or that are
related to diabetes
•Rare conditions such as decompression sickness,
anemia, burns, carbon monoxide poisoning, or
emboli from air or gas, etc.