Dataset Information

Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation.

ABSTRACT:

Background and purpose

Inflammatory and fibrogenic processes play a crucial role in the radiation-induced injury in the lung. The aim of the present study was to examine whether additive LPS exposure in the lung (to simulate respiratory infection) would affect pneumonitis or fibrosis associated with lung irradiation.

Material and methods

Wildtype C57Bl/6J (WT-C57) and TNF?, TNFR1 and TNFR2 knockout ((-/-)) mice, in C57Bl/6J background, were given whole thorax irradiation (10 Gy) with or without post-irradiation intratracheal administration of LPS (50?g/mice). Functional deficit was examined by measuring breathing rate at various times after treatment. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to analyze the protein expression and m-RNA of Interleukin-1 alpha (IL-1?), Interleukin-1 beta (IL-1?), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNF?) and Transforming Growth Factor beta (TGF?) in the lung at various times after treatment. Inflammatory cells were detected by Mac-3 (macrophages) and Toluidine Blue (mast cells) staining. Collagen content was estimated by hydroxyproline (total collagen) and Sircol assay (soluble collagen). Levels of oxidative damage were assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG) staining.

Results

LPS exposure significantly attenuated the breathing rate increases following irradiation of WT-C57, TNFR1(-/-) and TNFR2(-/-)mice and to a lesser extent in TNF?(-/-) mice. Collagen content was significantly reduced after LPS treatment in WT-C57, TNFR1(-/-) and TNF?(-/-) mice and there was a trend in TNFR2(-/-) mice. Similarly there were lower levels of inflammatory cells and cytokines in the LPS treated mice.

Conclusions

This study reveals a mitigating effect of early exposure to LPS on injury caused by irradiation on lungs of C57Bl mice. The results suggest that immediate infection post irradiation may not impact lung response negatively in radiation-accident victims, however, further studies are required in different animal models, and with specific infectious agents, to confirm and extend our findings.

SUBMITTER: Zaidi A

PROVIDER: S-EPMC3632095 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation.

Zaidi Asif A Jelveh Salomeh S Mahmood Javed J Hill Richard P RP

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20120914 3

<h4>Background and purpose</h4>Inflammatory and fibrogenic processes play a crucial role in the radiation-induced injury in the lung. The aim of the present study was to examine whether additive LPS exposure in the lung (to simulate respiratory infection) would affect pneumonitis or fibrosis associated with lung irradiation.<h4>Material and methods</h4>Wildtype C57Bl/6J (WT-C57) and TNFα, TNFR1 and TNFR2 knockout ((-/-)) mice, in C57Bl/6J background, were given whole thorax irradiation (10 Gy) w ...[more]

PMID: 22985778

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Project description:We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA receptor glutamatergic neurotransmission after NMDA receptor antagonism by ketamine. NBQX administered at the dose of 10 mg/kg intraperitoneally 15 min before ketamine in mice treated with LPS 24 h earlier restored LPS-induced decreased sucrose preference. These findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

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Dataset Information

Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation.

Background and purpose

Material and methods

Results

Conclusions

Publications

Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation.

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