When normal tissue is exposed to radiation, a complex series of biological events unfolds that can lead to damage at the cellular and molecular levels. Radiation primarily affects cells by depositing energy that causes ionization, which can directly break DNA strands or generate reactive oxygen species (ROS) that indirectly damage cellular components. The immediate consequence is often DNA damage, including single- and double-strand breaks, which if unrepaired or misrepaired, can lead to cell death or mutations.
Normal tissues vary in their sensitivity to radiation, largely depending on the rate of cell division. Tissues with rapidly dividing cells—such as the skin, lining of the gastrointestinal tract, and bone marrow—are more vulnerable because radiation disrupts the progenitor or stem cells responsible for replenishing mature cells. When these progenitor cells are destroyed or impaired, the tissue cannot maintain its normal structure and function, leading to early effects such as inflammation, cell loss, and impaired tissue regeneration.
At the cellular level, radiation can trigger apoptosis (programmed cell death), necrosis, or senescence. Apoptosis is often initiated by mitochondrial damage and the release of cytochrome c into the cytoplasm, activating cell death pathways. Radiation also induces oxidative stress by generating ROS, which attack lipids, proteins, and nucleic acids, further compromising cell viability. In some cases, lipid peroxidation—a damaging oxidative process affecting cell membranes—plays a critical role in tissue injury.
Beyond immediate cell death, radiation can provoke inflammatory responses. Damaged cells release signals that attract immune cells to the site, aiming to clear dead cells and initiate repair. However, this inflammation can also harm surrounding healthy tissue, exacerbating damage and sometimes leading to chronic conditions such as fibrosis (scarring). The extent and nature of inflammation vary depending on the radiation dose, the tissue type, and the radiation modality used.
Interestingly, newer radiation techniques like FLASH radiotherapy, which delivers ultra-high dose rates, have been shown to spare normal tissue more effectively than conventional radiation. This sparing effect is thought to be related to reduced lipid peroxidation and modulation of iron levels in normal cells, which limits oxidative damage. The protective mechanism of FLASH radiotherapy reduces inflammation and preserves normal tissue function while still effectively targeting cancer cells.
Over time, radiation-induced damage in normal tissue can manifest as delayed effects, including fibrosis, vascular damage, and impaired organ function. These late effects arise from chronic inflammation, altered tissue remodeling, and persistent cellular dysfunction. The severity depends on the total radiation dose, fractionation schedule, and individual tissue sensitivity.
In summary, when normal tissue is hit by radiation, it undergoes DNA damage, oxidative stress, cell death, and inflammation. Rapidly dividing tissues are most susceptible due to loss of progenitor cells. The inflammatory response, while part of healing, can also contribute to further tissue injury. Advances like FLASH radiotherapy show promise in reducing normal tissue damage by limiting oxidative stress and inflammation. However, radiation exposure can still lead to both immediate and long-term tissue changes that affect organ function.