21. Adaptations to hypoxia at cellular, tissue and organ level (HIFs). Main principles and mechanisms.

SYSTEMIC, ORGAN, CELLULAR ADAPTATIONS TO HYPOXIA

• Changes seen in cells due to hypoxia include:
• Mitochondrial changes - transition to highly permeable state
• Cytosolic changes - intracellular acidosis with secondary glycolytic block
• Nuclear changes - suppressed polymerases
• Lysosomal changes - destroyed lysosomes and their enzymes spill in the cytosol

Adaptations to hypoxia

General principles

• Adaptations are effective in light, relatively effective in medium, and ineffective in severe hypoxic states
• Adaptations are most stable in hypoxic hypoxia, less expressed in hemic and circulatory hypoxia and least stable in histotoxic hypoxia
• The following factors influence the expression and effectiveness of compensation:
• The degree and duration of hypoxia
• Pathogenetic factors forming different types of hypoxia
• Ontogenetic stage of the organism
• The hypoxic pattern - continuous, periodic, impulse, etc

1) Lung adaptations

• Increased lung and alveolar ventilation
• Hemoreflex mechanism
• Compensatory change in the relation ventilation/perfusion
• Increased pulmonary blood volume with higher O2 extraction in the alveoli
• Increased diffusion capacity of the alveolar-capillary membrane
• These all lead to more O2 brought to the organism

2) Cardiovascular adaptations

• Increased cardiac output
• Increased HR (tachycardia)
• Increased stroke volume
• Rise in the arterial blood pressure → better tissue perfusion
• Increased vascularisation and capillarisation
• Recruitment of reserve capillaries
• Formation of new capillaries
• Augmented transition of interstitial fluid to the vessels
• Better rheology of the blood
• Easy O2 diffusion
• These all lead to larger amounts of O2 transported and delivered to the cells

3) Blood adaptations

• They are among the most effective adaptations:
• Compensatory erythrocytosis
• Rapid - mobilisation of erythrocytes for the depots
• Slow - intense erythropoiesis as a result of erythropoietin production
• Adaptive change of O2 binding function of Hb
• High concentration of 2,3 diphosphoglycerate in erythrocytes → shift HB dissociation curve to the right → easier O2 release
• These all lead to more O2 bound and released per unit breathing area

4) Cellular adaptations

• Increased O2 reserve in the cells with O2 depots like myoglobin in muscles
• More effective delivery of electrons to transelectronase enzymes
• Increased O2 affinity of the terminal cytochrome oxidases
• Growing number of respiratory chains in a mitochondrion and mitochondria in a cell
• These all lead to complete extraction of all the O2 by the cells

HIF-1a (hypoxia inducible factor)

• Regulates normal need/consumption rate of oxygen in cells → activates oxidation processes and increases number of mitochondria
• Hypoxia inhibits HIF-1a which leads to the secretion of erythropoietin
• HIF-1a interacts closely with ERC, Hb, VEGF
• It is a translation factor → can activate/deactivate other enzymes