Thoracic radiation is an effective mainstay treatment for lung cancer, however patients risk developing an adverse side effect known as radiation-induced lung injury (RILI). RILI is dose-limiting, can be permanent, and may threaten normal lung function, but the underlying mechanism is not well characterized. RILI can include both inflammatory (radiation pneumonitis) and fibrotic (radiation-induced lung fibrosis) pathologies. Myofibroblasts are the main effector cells of fibrosis, and we and others have shown that ionizing radiation induces differentiation of normal lung fibroblasts to the myofibroblast phenotype (FMT, fibroblast to myofibroblast transdifferentiation). We previously reported that radiation induces production of excess lactate, which promotes an acidic microenvironment that activates the major profibrotic cytokine, transforming growth factor - β (TGFβ). TGFβ in turn upregulates production of lactate, creating a pro-fibrotic feed-forward loop. Here, we performed targeted metabolomics and metabolic tracer studies to determine how radiation alters cellular metabolism to promote fibrosis in cultured human lung fibroblasts and a mouse model of radiation induced lung fibrosis. Radiation upregulated both glycolysis and the pentose phosphate pathway (PPP), and we found that the PPP was a significant source of lactate production. Inhibition of glycolysis by targeting pyruvate kinase M2 prevented radiation-induced FMT and lactate production but did not affect fibronectin expression. However, when the gluconic shunt or the non-oxidative pentose phosphate pathway is blocked by targeting glucose-6-phosphate dehydrogenase, FMT, lactate production, and fibronectin are markedly reduced. Our data reveals that the PPP is an important compensatory mechanism and driver of lactate accumulation observed in RILI.
Odoom et al. (Fri,) studied this question.