Abstract
Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.
Highlights
Lung cancer remains the leading cause of cancer-related death in the USA
We proposed that the loss of sphingosine-1 phosphate (S1P), regulated enzymatically via sphingosine kinases 1 and 2 (SphK1/2) and sphingosine lyase (SphL), is directly linked to maladaptive lung repair and premature/accelerated cellular senescence, and it plays a critical role in radiation-induced lung disease [6]
We utilized an ex vivo model of organ culture whereby human donor lung slices that are representative of the in vivo tissue were kept alive in culture, as confirmed by the beating cilia of airway epithelial cells lining the bronchioles [17], to study the effect of LGM2605 treatment on proton radiation-induced lung damage, inflammation, and oxidative stress
Summary
Lung cancer remains the leading cause of cancer-related death in the USA. Radiation therapy plays a prominent role in the treatment of lung cancer patients, and the standard of care for locally-advanced non-small cell lung cancer (NSCLC) is chemoradiation [1,2]. Innovative advances in radiation therapy have resulted in novel modalities such as proton beam therapy, whereby higher doses of radiation are maintained on the tumor target, and tissue regions beyond the target volume are exposed to relatively low doses [3]. Despite these advances, there is a substantial risk of sub-acute and late side effects from damage to normal tissues, such as the pulmonary conditions of radiation pneumonitis and lung fibrosis, which can cause significant morbidity and mortality. As of yet no effective intervention or cure for radiation-induced late effects has been developed
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