Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues

Abstract

BackgroundDespite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT.ResultsCentral areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions.ConclusionsFocal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non-irradiated neighboring areas of lung tissue, indicating a global lung response to focal high-dose irradiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0338-9) contains supplementary material, which is available to authorized users.

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

“…To mimic the effects of clinical radiotherapy in an animal model of IR-induced lung damage, we had previously exposed mice lungs to high-dose radiation using a small-animal micro-irradiator (X-RAD320) equipped with a collimator system (to produce focal radiation beams) 7,8,28 . These studies showed that radiation pneumonitis occurs in mice within 2 weeks of exposure to 60-100 Gy of IR 8,15,28 .…”

“…Modern clinical radiotherapy techniques, including stereotactic radiotherapy (SBRT)-which delivers small fractions of ablative radiation doses-are more accurate and precise than conventional radiotherapy techniques. Previously, we had developed a mouse model that simulates SBRT; we used an image-guided smallanimal IR system to deliver a single high dose of radiation to the lung and verified the induction of pulmonary fibrosis in response to IR [6][7][8] .…”

“…Here, we examined the anti-inflammatory and anti-fibrotic properties of LXA 4 using a mouse model of RILI, wherein ablative radiation doses were delivered to the focal lung area using an image-guided IR system 6 , 7 , 26 – 28 . We also investigated whether LXA 4 regulates proteins that are important for EMT, particularly whether the crosstalk between LXA 4 -ALX/FPR2 and TGF-β/Smad signaling plays a key role in EMT.…”

Minimally invasive surgery is best treatment for early lung cancer

“…Assuming close to zero mortality and very limited morbidity of the surgical procedure, as typified by the study mentioned above, it does not seem realistic to think that the radiation technique can outperform surgery. The only way this seems possible is if the radiation somehow induces the patient's own immune system to help with cancer surveillance and treatment which has been suggested by some preclinical studies (3). Nonetheless this is quite a stretch and the reason most of the data coming out now that compares stereotactic radiation for small lung cancers with surgical resection favors surgical resection particularly when propensity-matching is done to balance the comparison populations.…”