Fig. 1. The proposed mechanism underlying radiation-induced fibrosis (RIF).

A) RT delivers ions that directly induces DNA damage and generates reactive oxygen species (ROS). Damaged cells in the skin and endothelium (colored purple) release cytokines, leading to activation of the innate and adaptive immune systems and recruitment of inflammatory cells. B) Once recruited to the irradiated area, neutrophils release additional inflammatory mediators to sustain inflammation. Lymphocytes and monocytes also migrate to the location of injury, the latter of which differentiate into macrophages. Macrophages, fibroblasts, native endothelial cells, and epidermal cells release transforming growth factor-beta (TGF-β) which stimulates fibroblasts to differentiate into myofibroblasts. C) Myofibroblasts secrete excess amounts of extracellular matrix proteins, leading to increased tissue stiffness and thickness. Over time, RIF ensues and may persist even decades after radiation therapy.