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Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

Lee SJ, Yi CO, Heo RW, Song DH, Cho YJ, Jeong YY, Kang KM, Roh GS, Lee JD - PLoS ONE (2015)

Bottom Line: Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0131671.g001: 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.

Mentions: Histopathologic changes were assesed in H&E- and Sirius red-stained lung sections (Fig 1A and 1B). Automated fibrosis scoring from the sirius red stained lung sections showed that the percentage of fibrosis in RT mice (185.51 ± 15.51) was increased compared with CTL mice (100.00 ± 12.10), whereas it was significantly inhibited by CLA administration (141.87 ± 8.11, p < 0.05). Compared with CTL mice, the influx of macrophages and interstitial edema in histologic sections were much greater in RT mice. However, both manifestations were inhibited by CLA administration. Likewise, scoring of macrophage influx, parenchymal collapse, consolidation, and alveolar epithelial cell changes were significantly higher in RT mice (vs CTL mice) and lower in RT + CLA mice (vs RT mice). Relative to CTL mice, fibrosis scores of RT mice were significantly higher (4.00 ± 0.24 vs 0.71 ± 0.18, p < 0.001); fibrosis scores of RT + CLA mice were significantly lower than those of RT mice (1.44 ± 0.53 vs 4.00 ± 0.24, p < 0.001) (Table 1). Radiation causes alveolar inflammatory cell apoptosis in lung injury [18]. To evaluate the effect of CLA on apoptosis in RILI, we performed western blot analysis using antibody to cleaved caspase-3, active caspase-3 (Fig 1C). We found that the expression level of cleaved caspase-3 in RT mice lung tissue were elevated compared with corresponding levels in lungs of CTL mice. However, its expression in RT mice was significantly reduced by CLA administration (Fig 1D).


Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

Lee SJ, Yi CO, Heo RW, Song DH, Cho YJ, Jeong YY, Kang KM, Roh GS, Lee JD - PLoS ONE (2015)

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4482753&req=5

pone.0131671.g001: 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.
Mentions: Histopathologic changes were assesed in H&E- and Sirius red-stained lung sections (Fig 1A and 1B). Automated fibrosis scoring from the sirius red stained lung sections showed that the percentage of fibrosis in RT mice (185.51 ± 15.51) was increased compared with CTL mice (100.00 ± 12.10), whereas it was significantly inhibited by CLA administration (141.87 ± 8.11, p < 0.05). Compared with CTL mice, the influx of macrophages and interstitial edema in histologic sections were much greater in RT mice. However, both manifestations were inhibited by CLA administration. Likewise, scoring of macrophage influx, parenchymal collapse, consolidation, and alveolar epithelial cell changes were significantly higher in RT mice (vs CTL mice) and lower in RT + CLA mice (vs RT mice). Relative to CTL mice, fibrosis scores of RT mice were significantly higher (4.00 ± 0.24 vs 0.71 ± 0.18, p < 0.001); fibrosis scores of RT + CLA mice were significantly lower than those of RT mice (1.44 ± 0.53 vs 4.00 ± 0.24, p < 0.001) (Table 1). Radiation causes alveolar inflammatory cell apoptosis in lung injury [18]. To evaluate the effect of CLA on apoptosis in RILI, we performed western blot analysis using antibody to cleaved caspase-3, active caspase-3 (Fig 1C). We found that the expression level of cleaved caspase-3 in RT mice lung tissue were elevated compared with corresponding levels in lungs of CTL mice. However, its expression in RT mice was significantly reduced by CLA administration (Fig 1D).

Bottom Line: Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus