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Gene expression analysis reveals inhibition of radiation-induced TGF?-signaling by hyperbaric oxygen therapy in mouse salivary glands.

ABSTRACT: A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significant attenuation of the radiation-induced expression of a set of genes and upstream regulators that are involved in processes such as fibrosis and tissue regeneration. Our data suggest that the TGF?-pathway, which is involved in radiation-induced fibrosis and chronic loss of function after radiation therapy, is affected by HBOT. On the longer term, HBOT reduced the expression of the fibrosis-associated factor ?-smooth muscle actin in irradiated salivary glands. This study highlights the potential of HBOT to inhibit the TGF?-pathway in irradiated salivary glands and to restrain consequential radiation induced tissue injury.

SUBMITTER: Spiegelberg L

PROVIDER: S-EPMC4107101 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Gene expression analysis reveals inhibition of radiation-induced TGFβ-signaling by hyperbaric oxygen therapy in mouse salivary glands.

Spiegelberg Linda L Swagemakers Sigrid M A SM Van Ijcken Wilfred F J WF Oole Edwin E Wolvius Eppo B EB Essers Jeroen J Braks Joanna A M JA

Molecular medicine (Cambridge, Mass.) 20140710

A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significa ...[more]

PMID: 24849810

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Project description:Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of TGFβ and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGFβ-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGFβ and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGFβ and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.

Dataset Information

Gene expression analysis reveals inhibition of radiation-induced TGF?-signaling by hyperbaric oxygen therapy in mouse salivary glands.

Publications

Gene expression analysis reveals inhibition of radiation-induced TGFβ-signaling by hyperbaric oxygen therapy in mouse salivary glands.

Similar Datasets

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