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...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2019/2750528 |
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| author | Xiao-Jing Ji Ji-Wei Hao Guang-Lei Li Ning Dong Xin-Qi Wang Min Zhou Qing-Hong Zhang Yong-Ming Yao |
| author_facet | Xiao-Jing Ji Ji-Wei Hao Guang-Lei Li Ning Dong Xin-Qi Wang Min Zhou Qing-Hong Zhang Yong-Ming Yao |
| author_sort | Xiao-Jing Ji |
| collection | DOAJ |
| 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 | Article |
| id | doaj-art-d7a7fc957d59480ca11b4317b28b55e4 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
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| series | Mediators of Inflammation |
| spelling | doaj-art-d7a7fc957d59480ca11b4317b28b55e42025-02-03T01:12:03ZengWileyMediators of Inflammation0962-93511466-18612019-01-01201910.1155/2019/27505282750528Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous SystemXiao-Jing Ji0Ji-Wei Hao1Guang-Lei Li2Ning Dong3Xin-Qi Wang4Min Zhou5Qing-Hong Zhang6Yong-Ming Yao7Trauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaNeurocritical Care Unit, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaTrauma Research Center, Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, ChinaBackground. 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.http://dx.doi.org/10.1155/2019/2750528 |
| spellingShingle | Xiao-Jing Ji Ji-Wei Hao Guang-Lei Li Ning Dong Xin-Qi Wang Min Zhou Qing-Hong Zhang Yong-Ming Yao Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System Mediators of Inflammation |
| 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 |
| url | http://dx.doi.org/10.1155/2019/2750528 |
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