Pathology

Hypoxia and Ischemia

 Hypoxia and Ischemia
Deficiency of oxygen leads to failure of many energy dependent
metabolic pathways, and ultimately to death of cells by necrosis.
Most cellular ATP is produced from adenosine diphosphate (ADP)
which is required for membrane transport, protein synthesis,
lipogenesis. It is estimated that in total, the cells of a healthy human
burn 50 to 75 kg of ATP every day! Not surprisingly, therefore, cells
deprived of oxygen are at risk of suffering catastrophic failure of many
essential functions. Oxygen deprivation is one of the most frequent
causes of cell injury and necrosis in clinical medicine.
Cells subjected to the stress of hypoxia that do not immediately die activate
compensatory mechanisms that are induced by hypoxia inducible factor 1 (HIF-1)
family. HIF-1 simulates the synthesis of several proteins that help the cell to survive
in the face of low oxygen.
Some of these proteins, such as vascular endothelial growth factor (VEGF),
stimulate the growth of new vessels and thus attempt to increase blood flow and
the supply of oxygen.
Other proteins induced by HIF-1 cause adaptive changes in cellular metabolism by
stimulating the uptake of glucose and glycolysis. Normal tissues with a greater
glycolytic capacity because of the presence of glycogen (e.g. liver) are more likely to
survive hypoxia and decreased oxidative phosphorylation than tissues with limited
glucose stores (e.g. brain).
Although, rapidly proliferating normal cells and cancer cells rely on aerobic
glycolysis to produce much of their energy, a phenomenon referred to as the
Warburg effect. The reason for this is that although glycolysis yields less ATP per
molecule of glucose burned than oxidative phosphorylation, metabolites generated
by glycolysis and the TCA cycle serve as precursors for the synthesis of cellular
constituents (e.g., proteins, lipids, and nucleic acids) that are needed for cell
growth and division.
Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation
and depletion of ATP in cells. Loss of this critical energy store has deleterious effects on
many cellular systems.
• Reduced activity of plasma membrane ATP-dependent sodium pumps, resulting in
intracellular accumulation of sodium and efflux of potassium. The net gain of solute is
accompanied by iso osmotic gain of water, causing cell swelling and dilation of the ER.
• The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation,
decreased intracellular pH, and decreased activity of many cellular enzymes.
• Prolonged or worsening depletion of ATP causes structural disruption of the protein
synthetic apparatus, manifested as detachment of ribosomes from the rough ER (RER),
with a consequent reduction in protein synthesis.
• It also has been suggested that hypoxia increases the accumulation of ROS. Hypoxia
predisposes cells to ROS-mediated damage if blood flow (and oxygen delivery) is
reestablished, a phenomenon called reperfusion injury.
• Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and
the cell undergoes necrosis. Although necrosis is the principal form of cell death caused by
hypoxia, apoptosis by the mitochondrial pathway is also thought to contribute.
The functional consequences of hypoxia and ischemia depend on the severity and duration
of the deficit. For instance, the heart muscle ceases to contract within 60 seconds of
coronary occlusion. If hypoxia continues, worsening ATP depletion causes further
deterioration, undergoing the sequence of changes illustrated.
 Ischemia-Reperfusion Injury
Under certain circumstances, the restoration of blood flow to ischemic but viable tissues
results, in increased cell injury. This is the reverse of the expected outcome of the
restoration of blood flow, which normally results in the recovery of reversibly injured cells.
This so-called “ischemia-reperfusion injury” is a clinically important process that may
contribute significantly to tissue damage, especially after myocardial and cerebral
ischemia.
Several mechanisms may account for the exacerbation of cell injury resulting from
reperfusion of ischemic tissues:
• New damage may be initiated during reoxygenation by increased generation of ROS.
Some of the ROS may be generated by injured cells with damaged mitochondria that
cannot carry out the complete reduction of oxygen, and at the same time cellular anti-
oxidant defense mechanisms may be compromised by ischemia, exacerbating the
situation. ROS generated by infiltrating leukocytes also may contribute to the damage of
vulnerable injured cells.
• The inflammation that is induced by ischemic injury may increase with reperfusion
because it enhances the influx of leukocytes and plasma proteins. The products of
activated leukocytes may cause additional tissue injury. Activation of the complement
system also may contribute to ischemia-reperfusion injury. Complement proteins may bind
to the injured tissues, or to antibodies that are deposited in the tissues, and subsequent
complement activation generates byproducts that exacerbate the cell injury and
inflammation.
The functional and morphologic consequences of hypoxia and ischemia. ER,
Endoplasmic reticulum.
The principal biochemical mechanisms and sites of damage in cell injury. Note that causes and
mechanisms of cell death by necrosis and apoptosis are independent but there may be overlap.