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Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System
BACKGROUND: Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic n...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360064/ https://www.ncbi.nlm.nih.gov/pubmed/30800001 http://dx.doi.org/10.1155/2019/2750528 |
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author | Ji, Xiao-Jing Hao, Ji-Wei Li, Guang-Lei Dong, Ning Wang, Xin-Qi Zhou, Min Zhang, Qing-Hong Yao, Yong-Ming |
author_facet | Ji, Xiao-Jing Hao, Ji-Wei Li, Guang-Lei Dong, Ning Wang, Xin-Qi Zhou, Min Zhang, Qing-Hong Yao, Yong-Ming |
author_sort | Ji, Xiao-Jing |
collection | PubMed |
description | BACKGROUND: Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. METHODS: Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of β-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 μmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. RESULTS: Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. CONCLUSIONS: Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury. |
format | Online Article Text |
id | pubmed-6360064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-63600642019-02-24 Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System Ji, Xiao-Jing Hao, Ji-Wei Li, Guang-Lei Dong, Ning Wang, Xin-Qi Zhou, Min Zhang, Qing-Hong Yao, Yong-Ming Mediators Inflamm Research Article BACKGROUND: Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. METHODS: Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of β-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 μmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. RESULTS: Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. CONCLUSIONS: Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury. Hindawi 2019-01-17 /pmc/articles/PMC6360064/ /pubmed/30800001 http://dx.doi.org/10.1155/2019/2750528 Text en Copyright © 2019 Xiao-Jing Ji et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Ji, Xiao-Jing Hao, Ji-Wei Li, Guang-Lei Dong, Ning Wang, Xin-Qi Zhou, Min Zhang, Qing-Hong Yao, Yong-Ming Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title | Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title_full | Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title_fullStr | Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title_full_unstemmed | Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title_short | Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System |
title_sort | exendin-4 exacerbates burn-induced morbidity in mice by activation of the sympathetic nervous system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360064/ https://www.ncbi.nlm.nih.gov/pubmed/30800001 http://dx.doi.org/10.1155/2019/2750528 |
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