Biological basis of radiation-induced pulmonary fibrosis

Sottili Mariangela, Mangoni Monica, Terziani Francesca, Trombetta Laura, Loi Mauro, Cappelli Sabrina, Di Brina Lucia, Livi Lorenzo


Pulmonary fibrosis is a major radiotherapy-related toxicity, that worsens patients’ quality of life, eventually leading to reduced treatment doses and subsequent decreased cancer control probability. Current therapies for radiation-induced pulmonary fibrosis are largely ineffective; thus, intense research has been done to elucidate the pathogenesis of pulmonary fibrosis and develop therapeutic strategies able to mitigate this severe side effect without interfering with anticancer treatment. The development of radiation-induced pulmonary fibrosis involves multifactorial complex processes. The severity of the response to lung irradiation is influenced by the dose of radiation, the volume of the irradiated parenchyma, the simultaneous use of chemotherapy, preexisting lung diseases, and age and genetic predispositions. Moreover, ionizing irradiation activates a cascade of genetic and nongenetic events involving several cell types, such as pneumocytes, endothelial cells, myofibroblasts and immune cells. This complex radiation-induced biological response is mediated by numerous cross-talking signaling pathways and molecules, including the TGF-β system, cytokines, the NF-kB network, and free-radicals. However, despite the recent progress made in understanding the molecular and cellular mechanisms underlying pathophysiology of lung injury after radiation exposure, much remains to be learned about how the various cells and signaling pathways interact. Thus, further studies are needed to identify reliable markers and effective targets, with the aim of developing therapeutic approaches able to prevent or treat this severe condition.

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