Figure 10

Pathways by which BrdU impairs epithelial repair and induces persistent inflammation in the chronic NA injury model. BrdU induces genotoxic stress, which activates the DNA damage response, thereby promoting premature senescence, which results in the growth arrest of epithelial cells. Genotoxic stress caused by BrdU also activates p38-MAPK pathways that trigger the production of pro-inflammatory cytokines/chemokines, which exacerbate inflammation. Which is necessary for p38-MAPK activation, the DNA damage response or cell cycle arrest (p21, etc.), has not been determined (broken arrows). Recent evidence indicates that pro-inflammatory cytokines (e.g., IL-6, IL-8) at least in part reinforce cell cycle arrest via the DNA damage response pathway [32, 33], suggesting a positive feedback loop (dashed arrow) in which inflammation in turn promotes senescence.