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The Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates Radiation-Induced Lung Injury in a Mouse Model

Abstract

Radiation-induced lung injury (RILI) is a potentially life-threatening complication of radiotherapy. In the current study, we examined the potential protective effects of URB937, an inhibitor of fatty acid amide hydrolase using a mouse model of RILI. Briefly, male C57BL/6 mice received 16Gy irradiation to the thoracic region and then intraperitoneal injection of either URB937 (1 mg/kg) or vehicle every 2 days for 30 days. The extent of the lung injury was evaluated histologically at the end of the drug treatment as well as 3 months after the cessation of the treatment. The data showed URB937 attenuated radiation-induced lung injury and increased endocannabinoid concentration in lung tissue. Treatment with URB937 decreased leukocyte migration and inflammatory cytokines in bronchoalveolar lavage fluid and plasma at day 30. Histopathological examination revealed URB937 could restore lung structure and restrain inflammatory cell and fibroblast accumulation caused by irradiation in lung tissue. URB937 also decreased radiation-induced pro-inflammatory (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α) and pro-fibrotic cytokines (e.g., transforming growth factor-β1) level in lung tissue, as well as lipid peroxidation in the lungs. Mouse survival examined in a separate group of experimental subjects indicated that URB937 could prolong animal survival. Experiments using a mouse bearing Lewis lung carcinoma cells showed that URB937 does not affect irradiation-induced inhibition of tumor growth. These results suggest that inhibiting fatty acid amide hydrolase could ameliorate RILI without compromising the efficacy of irradiation on tumor control.

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Abbreviations

RILI:

Radiation-induced lung injury

MDA:

Malondialdehyde

ROS:

Reactive oxygen species

TGF-β:

Transforming growth factor

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

AEA:

Anandamide

FAAH:

Fatty acid amide hydrolase

H&E:

Hematoxylin and eosin

BLAF:

Bronchoalveolar lavage fluid

LLCs:

Lewis lung carcinoma cells

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81472808, No.81301935, No.81472196).

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Correspondence to Jianxin Xue or You Lu.

Ethics declarations

The use of C57BL/6J mice was approved by Animal Care and Use Committee of Sichuan University.

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The authors declare that they have no conflicts of interests.

Additional information

Rui Li and Guo Chen contributed equally to this work.

Electronic Supplementary Material

ESM 1

pdf: URB937 specific synthetic route. URB937 was synthesized in this laboratory. (PDF 169 kb)

ESM 2

pdf: The sequences of qRT-PCR primers. (PDF 843 kb)

ESM 3

pdf: The preliminary data of URB937 dose chosen. (PDF 25095 kb)

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Li, R., Chen, G., Zhou, L. et al. The Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates Radiation-Induced Lung Injury in a Mouse Model. Inflammation 40, 1254–1263 (2017). https://doi.org/10.1007/s10753-017-0568-7

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KEY WORDS

  • radiation-induced lung injury
  • endocannabinoids
  • RILI
  • radiation pneumonia
  • pulmonary fibrosis