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. 2015 Jun 26;10(6):e0131671.
doi: 10.1371/journal.pone.0131671. eCollection 2015.

Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice

Seung Jun Lee  1 , Chin-ok Yi  2 , Rok Won Heo  2 , Dae Hyun Song  3 , Yu Ji Cho  1 , Yi Yeong Jeong  1 , Ki Mun Kang  4 , Gu Seob Roh  2 , Jong Deog Lee  1
Affiliations

Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice

Seung Jun Lee et al. PLoS One. .

Abstract

Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Effects of clarithromycin on radiation-induced macrophage influx, alveolar septal changes, and apoptosis in lungs of mice.
(A) Representative photomicrographs of H&E-stained lung sections from control (CTL), radiation only (RT), radiation + clarithromycin (RT+CLA), and clarithromycin only (CLA) animal groups (macrophage at arrow). (B) Representative photomicrographs of sirius red-stained lung sections from each group. Thin arrow indicates macrophage and bold arrow indicates thickened, fibrotic alveolar septum). Scale bar = 100μm. (C) Cleaved caspase-3 expression in lungs of control (CTL), radiation only (RT), radiation + clarithromycin (RT+CLA), and clarithromycin only (CLA) animal groups. (D) Cleaved caspase-3 expression in lungs of respective groups. Densitometry values were normalized to β-actin and data are presented as mean ± SEM (n = 2–6 mice per group). *p<0.05 vs CTL mice; †p<0.05 vs RT mice.
Fig 2
Fig 2. Effects of clarithromycin on inflammation in irradiated lungs of mice.
(A) TNF-α expression in lungs of control (CTL), radiation only (RT), radiation + clarithromycin (RT + CLA), and clarithromycin only (CLA) animal groups. (B) TNFR1 and TNFR2 expression in lungs of respective groups. (C and D) Acetylated NF-κB p65 and (E) COX-2 expression in lungs of respective groups. Densitometry values were normalized to β-actin and data are presented as mean ± SEM (n = 2–6 mice per group). *p<0.05 vs CTL mice; †p<0.05 vs RT mice. (F) Immunostained COX-2 in lung tissue by group. Scale bar = 100 μm.
Fig 3
Fig 3. Effects of clarithromycin on VCAM-1 and MMP-9 expression levels in irradiated lungs of mice.
(A) VCAM-1 expression in lungs of control (CTL), radiation only (RT), radiation + clarithromycin (RT+CLA), and clarithromycin only (CLA) animal groups. (B) MMP-9 expression in lungs of respective groups. Densitometry values were normalized to β-actin and data are presented as mean ± SEM (n = 2–6 mice per group). *p<0.05 vs CTL mice; †p<0.05 vs RT mice.
Fig 4
Fig 4. Effects of clarithromycin on Nrf2 and HO-1 expression levels and on HO-1 immunoreactivity in irradiated lungs of mice.
(A) Nrf2 and HO-1 expression levels in lungs of control (CTL), radiation only (RT), radiation + clarithromycin (RT+CLA), and clarithromycin only (CLA) animal groups. Densitometry values were normalized to β-actin and data are presented as mean ± SEM (n = 2–6 mice per group). *p<0.05 vs CTL mice; †p<0.05 vs RT mice. (B) Immunostained HO-1 in lung tissue by group. Scale bar = 100 μm.
Fig 5
Fig 5. Effects of clarithromycin on TGFβ-1, CTGF, and collagen type I gene expressions and on tissue collagen concentration.
(A) TGFβ-1 expression in lungs of control (CTL), radiation only (RT), radiation + clarithromycin (RT+CLA), and clarithromycin only (CLA) animal groups. (B) CTGF and collagen type I gene expressions in lungs of respective groups. Densitometry values were normalized to β-actin and data are presented as mean ± SEM (n = 2–6 mice per group). (C) Collagen concentration in lung tissue by group (n = 2–9 mice per group, Sircol collagen assay). *p<0.05 vs CTL mice; †p<0.05 vs RT mice.
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Grants and funding

This study was supported by a grant of the Basic Science Research Program through the National Research Foundation of Korea (No. 2014R1A2A1A11049588).