The Cellular and Molecular Mechanism of Radiation-Induced Lung Injury

The purposes of this study were 1) to identify the nitric oxide (NO) synthase (NOS) isoform responsible for NO-mediated radiation-induced lung injury, 2) to examine the formation of nitrotyrosine, and 3) to see whether nitrotyrosine formation and lung injury are reduced by an inducible NOS (iNOS) inhibitor, aminoguanidine. The left hemithorax of rats was irradiated (20 Gy), and the degree of lung injury, the expression of NOS isoforms, and the formation of nitrotyrosine and superoxide were examined after 2 wk. iNOS mRNA was induced, and endothelial NOS mRNA was markedly increased in the irradiated lung. Nitrotyrosine was detected biochemically and immunohistochemically. Aminoguanidine prevented acute lung injury as indicated by decreased protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid and improved NMR parameters and histology. Furthermore, the formation of nitrotyrosine was significantly reduced in the aminoguanidine group. We conclude that iNOS induction is a major factor in radiation-induced lung injury and that nitrotyrosine formation may participate in the NO-induced pathogenesis.

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An Experimental Model-Based Biomarker Exploration of Radiation-Induced Lung Injury In Vivo and In Vitro

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2013.06.1760 ◽

2013 ◽

Vol 87 (2) ◽

pp. S664 ◽

Cited By ~ 1

Author(s):

Z. Hong ◽

K. Song ◽

M. Story ◽

J. Cho

Keyword(s):

Lung Injury ◽

Experimental Model ◽

Model Based ◽

Radiation Induced

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Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Brazilian Journal of Medical and Biological Research ◽

10.1590/1414-431x20132856 ◽

2013 ◽

Vol 46 (9) ◽

pp. 789-796 ◽

Cited By ~ 10

Author(s):

B.H. Bakkal ◽

F.A. Gultekin ◽

B. Guven ◽

U.O. Turkcu ◽

S. Bektas ◽

...

Keyword(s):

Lung Injury ◽

Radiation Induced ◽

Early Radiation

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Ionizing radiation enhances matrix metalloproteinase-2 production in human lung epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l30 ◽

2001 ◽

Vol 280 (1) ◽

pp. L30-L38 ◽

Cited By ~ 41

Author(s):

Jun Araya ◽

Muneharu Maruyama ◽

Kazuhiko Sassa ◽

Tadashi Fujita ◽

Ryuji Hayashi ◽

...

Keyword(s):

Epithelial Cells ◽

Ionizing Radiation ◽

Basement Membrane ◽

Lung Injury ◽

Human Lung ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Radiation Induced ◽

Human Lung Epithelial Cells

Radiation pneumonitis is a major complication of radiation therapy. However, the detailed cellular mechanisms have not been clearly defined. Based on the recognition that basement membrane disruption occurs in acute lung injury and that matrix metalloproteinase (MMP)-2 can degrade type IV collagen, one of the major components of the basement membrane, we hypothesized that ionizing radiation would modulate MMP-2 production in human lung epithelial cells. To evaluate this, the modulation of MMP-2 with irradiation was investigated in normal human bronchial epithelial cells as well as in A549 cells. We measured the activity of MMP-2 in the conditioned medium with zymography and the MMP-2 mRNA level with RT-PCR. Both of these cells constitutively expressed 72-kDa gelatinolytic activity, corresponding to MMP-2, and exposure to radiation increased this activity. Consistent with the data of zymography, ionizing radiation increased the level of MMP-2 mRNA. This radiation-induced increase in MMP-2 expression was mediated via p53 because the p53 antisense oligonucleotide abolished the increase in MMP-2 activity as well as the accumulation of p53 after irradiation in A549 cells. These results indicate that MMP-2 expression by human lung epithelial cells is involved in radiation-induced lung injury.

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Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

Cell Death Discovery ◽

10.1038/s41420-021-00791-8 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Ni An ◽

Zhenjie Li ◽

Xiaodi Yan ◽

Hainan Zhao ◽

Yajie Yang ◽

...

Keyword(s):

Ionizing Radiation ◽

Lung Injury ◽

Mouse Model ◽

Tumor Cells ◽

Nuclear Translocation ◽

Lung Tumor ◽

Lung Epithelial Cells ◽

Normal Lung ◽

Limiting Factor ◽

Radiation Induced

AbstractThe lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

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