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Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells.

ABSTRACT: Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.

SUBMITTER: Hansel C

PROVIDER: S-EPMC8268757 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells.

Hansel Christine C Barr Samantha S Schemann Alina V AV Lauber Kirsten K Hess Julia J Unger Kristian K Zitzelsberger Horst H Jendrossek Verena V Klein Diana D

International journal of molecular sciences 20210630 13

Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression o ...[more]

PMID: 34209135

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Project description:ObjectiveRadiation-induced lung injury (RILI) is a serious side-effect of radiotherapy for lung cancer, in which effects on the normal lung epithelium may play a key role. Since these effects are incompletely understood, the aim of the present study was to evaluate the effect of ionizing radiation (IR) on cultured well-differentiated primary bronchial epithelial cells (PBEC) with a focus on cytotoxicity, barrier formation, inflammation and epithelial progenitor function.Materials and methodsPBEC were cultured at the Air-Liquid Interface (ALI-PBEC) to allow mucociliary differentiation. Effect of IR (1, 2, 4, 8 Gy [Gy]) on ALI-PBEC cultures was investigated by lactate dehydrogenase (LDH) release, Trans Epithelial Electrical Resistance (TEER; as a measure of barrier function), qPCR (P21/CDKNA1, MKI67, AEN, E2F1, ATF3) and immunofluorescence staining (γH2Ax-foci). The impact on epithelial progenitor function was assessed by studying organoid formation capacity of irradiated ALI-PBEC at 24 h and 7 days after IR.Results and discussionIR increased the number of γH2Ax-foci (marker of double stranded DNA breaks) in ALI-PBEC, but did not affect markers of toxicity (LDH-release or TEER). IR did also not affect mRNA markers for inflammation or epithelial-mesenchymal transition (EMT), but did increase mRNA levels of the cell cycle inhibitor P21/CDKN1A and resulted in downregulation of the proliferation markers MKI67 and E2F1. Finally, IR of ALI-PBEC had a marked effect on organoid formation capacity, which was markedly impaired following IR in a dose-dependent manner.ConclusionIn conclusion, epithelial progenitor cell function as assessed by organoid formation capacity is strongly reduced by IR and persists for at least 7 days. Despite an effect on organoid formation capacity, DNA breaks, P21/CDKN1A expression and reduced expression of MKI67 and E2F1, this effect was not accompanied by IR-induced cytotoxicity, or an increase in markers of inflammation or EMT. This study indicates that studying the effects of IR on organoid formation is a valid and sensitive tool to study adverse effects of IR on normal lung epithelial cells and could be used as a tool to study RILI.

Dataset Information

Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells.

Publications

Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells.

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