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Molecular hydrogen attenuates gefitinib-induced exacerbation of naphthalene-evoked acute lung injury through a reduction in oxidative stress and inflammation

Laboratory Investigation (2019) | Download Citation

Abstract

Although inhibition of epidermal growth factor receptor (EGFR)-mediated cell signaling by the EGFR tyrosine kinase inhibitor gefitinib is highly effective against advanced non-small cell lung cancer, this drug might promote severe acute interstitial pneumonia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive anti-oxidant. Here, we show that treatment with H2 effectively protects the lungs of mice from severe damage caused by oral administration of gefitinib after intraperitoneal injection of naphthalene, the toxicity of which is related to oxidative stress. Drinking H2−rich water ad libitum mitigated naphthalene/gefitinib-induced weight loss and significantly improved survival, which was associated with a decrease in lung inflammation and inflammatory cytokines in the bronchoalveolar lavage fluid. Naphthalene decreased glutathione in the lung, increased malondialdehyde in the plasma, and increased 4-hydroxy-2-nonenal production in airway cells, all of which were mitigated by H2-rich water, indicating that the H2-rich water reverses cellular damage to the bronchial wall caused by oxidative stress. Finally, treatment with H2 did not interfere with the anti-tumor effects of gefitinib on a lung cancer cell line in vitro or on tumor-bearing mice in vivo. These results indicate that H2-rich water has the potential to improve quality of life during gefitinib therapy by mitigating lung injury without impairing anti-tumor activity.

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Acknowledgements

We thank Naoki Maruyama for his continuous encouragement and support. This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (Grant numbers 16K16616 and 16H03267).

Author information

Affiliations

  1. Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan

    • Yasuhiro Terasaki
    • , Mika Terasaki
    • , Naomi Kuwahara
    • , Yusuke Kajimoto
    •  & Akira Shimizu
  2. Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    • Tetsuya Suzuki
    • , Kozue Tonaki
    • , Jumi Ohsiro
    • , Masumi Iketani
    • , Mayumi Takahashi
    •  & Ikuroh Ohsawa
  3. Department of Life Sciences, Faculty of Life Science, Toyo University, Gunma, Japan

    • Tetsuya Suzuki
    • , Jumi Ohsiro
    •  & Hideo Kawaguchi
  4. Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan

    • Kozue Tonaki
    •  & Seisuke Hattori
  5. Department of Physiology, Toho University School of Medicine, Tokyo, Japan

    • Makoto Hamanoue

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The authors declare that they have no conflict of interest.

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Correspondence to Ikuroh Ohsawa.

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https://doi.org/10.1038/s41374-019-0187-z