Pathophysiology And Mediators Of Late Effects

As discussed in the equivalent section of early effects, radiation causes acute damage to cell proteins and DNA, either directly or indirectly. These effects may lead to cell cycle arrest, activation of repair pathways, release of cytokines, and cell death through numerous mechanisms. The time for these effects to become clinically apparent (the latency is what classes effects as early or late. In general, early effects are due to death of stem cells in rapidly renewing tissues (such as epithelial layers) or from cytokine release and inflammation (oedema, erythema, fatigue). Late effects may still occur due to these mechanisms, but are often more complex:

  • Slowly proflierating tissues may take more time to demonstrate damage from radiation due to cell loss, as DNA damage may not lead to death until the cell attempts to divide
  • Migration of inflammatory cells and intercommunication between cells through cytokines has a significant role to play in many late effects
  • Damage to connective tissue cells within the treatment field often takes some time to manifest due to the long life of these cells (endothelial cells, fibrocytes/blasts)
  • Damage to the genome which is not fatal, ie: radiation carcinogenesis and hereditary effects

In summary, the effects of radiation on normal tissue are classified as early or late depending on the time it takes for clinical features to become apparent. Early effects occur due to rapid processes, such as an acute inflammatory response or death of stem cells supplying a rapidly renewing tissue. Late effects occur due to processes that take significant time to develop, either because the tissue renews slowly, their relation to connective tissue cells, chronic inflammatory processes or genomic damage.

Death of Stem Cells

In a similar method to early effects, radiation may induce death of stem cells in slowly dividing tissues. These stem cells of these tissues (or their progeny) have such a long life span that radiation effects do not become apparent for months, years or decades.

Cytokines and Inflammatory Changes

Early effects such as erythema and fatigue are thought tobe due to the acute release of cytokines by irradiated cells. This causes endothelial dilatation and migration of inflammatory cells into the region. Once radiation has been completed, there is still an interplay of cytokine signalling between the parenchymal cells, fibrocytes, endothelial cells and inflammatory cells that remain in the tissue. This interaction is thought to be of significant importance in the development of late effects, and is discussed in the Cytokines involved in Late Effects topic.

Effects on Connective Tissues

The connective tissues of an organ are a frequent cause of late effects. The endothelial cells and fibroblasts are the primary targets.

Endothelial Cells

Endothelial cells have a long life expectancy and divide rarely. If exposed to radiation, they may therefore die at a time distant to the exposure. Loss of endothelial cells leads to proliferation of the surviving cells. This can lead to:

  • Constriction of capillaries due to proliferating cells
  • Thrombosis and fibrosis due to bare areas of vessel walls

These changes lead to hypoxia of the parenchymal cells or haemorrhage, which cause damage to the parenchymal cells with loss of their function. Telangiectasia, which is the formation of large dilated capillaries in the superficial mucosa, is due to a combination of endothelial cell loss (and resulting dilatation of vessels) coupled with insufficient supply of the overlying epithelium (leading to thinning).

Fibroblasts

Genetic Damage

The DNA is the target of radiation, and sufficient damage leads to cell death. Cells may survive radiation exposure in one of two ways:

  • Repairing the damage
  • Not recognising the damage - if the damage is not fatal to the cell it may be 'missed' by repair pathways

Repair is not a process without faults and it is possible that surviving cells may carry mutations. If these mutations occur in sensitive parts of the DNA, there is potential for radiation carcinogenesis or hereditary effects (only if gametes are involved).