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H y p o x i a

Lecturer: Oleh Myronenko,

Department of Pathophysiology,

Bogomolets NMU

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AIMS are:

  • To find out the definition, classification and etiology of hypoxia

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  • To study compensatory and pathological mechanisms in hypoxia

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  • To investigate the main consequences of hypoxia

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Hypoxia is one of the most common pathological processes…

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  • Hypoxia is an inadequate oxygen supply to tissues and/or disturbed oxygen consumption (utilization) by cells.

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  • Hypoxemia is the decreased partial pressure of oxygen in arterial blood (PaO2).
  • Dyspnea is a subjective experience of breathing discomfort (sensation of lack or excess of air in the lungs).

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Gases exchange �(A-alveolar, a-arterial)

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  • SaO2 – saturation, an average percentage of oxygen bound to Hb in the RBCs [OxyHb/(OxyHb+DeoxyHb)]
  • PaO2 – partial pressure of oxygen in arterial blood
  • 1,34 mL O2 / g Hb – oxygen carrying capacity
  • 0,003 mL / mmHg O2 / dL of blood – oxygen solubility coefficient in blood

Content of O2 in the blood =

= (1,34*[Hb])*SaO2 + 0,003*PaO2

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Classification of hypoxia:

  • According to the course: acute/chronic.
  • According to prevalence: local/general (systemic).
  • According to etiology: hypoxic (exogenous), respiratory, circulatory (cardiovascular), hemic (blood), tissue (histotoxic) and mixed.

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Type

Characteristics

Examples

Exogenous (hypoxic) hypoxia

pO2 ↓; SaO2 ↓; pCO2 ↓; respiratory alkalosis due to hyperventilation; spasm of cerebral arteries; high-altitude cerebral edema (HACE); high-altitude pulmonary edema (HAPE)

Mountain disease, high altitude disease, lack of oxygen in closed chambers etc.

Respiratory hypoxia

pO2 ↓; SaO2 ↓; pCO2 ↑; respiratory acidosis; dilation of cerebral arteries

Respiratory failure: ventilation, diffusion and perfusion disorders (pneumonia etc.)

Circulatory hypoxia

Arteriovenous oxygen difference ↑; SaO2 ↓; metabolic acidosis (lactate accumulation due to anaerobic glycolysis)

Systemic – heart failure, shock; local – ischemia, congestion etc.

Haemic (blood) hypoxia

[Hb] ↓ and/or SaO2 ↓, but normal pO2; metabolic acidosis

Anemias (blood loss, hemolysis etc.); inactivation of Hb (e.g., pathological type of Hb in case of CO poisoning)

Tissue (histotoxic) hypoxia

Arteriovenous oxygen difference ↓; normal levels of pO2 and SaO2 ; metabolic acidosis

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Inactivation of respiratory chain enzymes; uncoupling oxidative phosphorylation (e.g., dinitrophenol)

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Chocolate brown blood in case of ↑ MetHb (right)

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CO and cyanide (CN) specifically inhibit cytochrome oxidase in complex IV of the ETC �(respiratory chain)

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Fast compensatory mechanisms in hypoxia:

  • Hyperventilation
  • Cardiac output ↑, accelerated heart rate
  • Release of blood from the depot
  • O2-binding curve (OBC) shift
  • Vasodilation (local effect)
  • Increased affinity of respiratory chain enzymes (cytochromes) to oxygen in mitochondria

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Delayed compensatory mechanisms in hypoxia:

  • Hypertrophy of respiratory muscles
  • Cardiac hypertrophy
  • Bone marrow hyperplasia and erythrocytosis (elevated RBCs count)
  • Formation of new vessels (local effect)
  • Hypertrophy of mitochondria in cells
  • Increased expression of glycolysis enzymes, respiratory chain enzymes etc.

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HIF-1 (hypoxia inducible factor)

is the main molecular sensor and regulator of hypoxia response in cells

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HIFs (trough HRE):

  • Shift to anaerobic metabolism (glycolytic enzymes ↑)
  • Glucose transporters ↑
  • Vascularization (VEGF) ↑
  • Erythropoietin (EPO) ↑
  • Apoptosis ↑ in case of overexpression (stabilization of p53)
  • Fibrosis (TGF-β ↑)

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Mechanisms of hypoxic cell injury:

  • ATP depletion
  • Ca2+ overload
  • Osmotic mechanism (cell swelling)
  • Intracellular acidosis
  • ROS (free radicals) production ↑

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Reperfusion syndrome

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Negative consequences of hypoxia:

1) Organ dysfunction (inability to perform normal metabolic functions)

2) Atrophy (reduction in cell/tissue mass)

3) Infarction of tissue (localized area of tissue necrosis)

4) Organ fibrosis/sclerosis (accumulation of connective tissue)

5) Death (in case of systemic hypoxia)

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Cyanosis (clinical sigh of systemic hypoxia, SaO2˂80%)

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The most susceptible to hypoxia tissues:

  • Neurons in the central nervous system (irreversible damage occurs in 5 min. after global hypoxia), especially the area between the distribution of the anterior and middle cerebral arteries
  • Subendocardial tissue (coronary vessels penetrate the epicardial surface)
  • Renal cortex and medulla (especially the straight portion of the proximal tubule in the cortex and the thick ascending limb of the medulla)
  • Hepatocytes located around the central venule

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Watershed infarction in brain

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CONCLUSIONS:

  • Hypoxia is the most common typical pathological process.

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  • The main types of hypoxia are exogenous, respiratory, circulatory, hemic, histotoxic and mixed.

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  • The main molecular response to hypoxia is stabilization of HIF-1 and activation of genes expression to compensate lack of oxygen on different levels – from cell to whole body.

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References:

  • Robbins Basic Pathology – 10 Ed., 2017.
  • Sue E. Huether, Kathryn L. McCance: Understanding Pathophysiology - 6 Ed., 2017.
  • Crowley's An Introduction To Human Disease - 10th Ed., 2017.
  • Lee-Ellen Copstead: Pathophysiology – �5 Ed., 2013