Objective: To establish an animal model for posttraumatic stress disorder in burn-injured patients. Methods: Thermal-injured mice with 15% total body surface area were subjected to a series of neurobehavioral tests at 1 and 3 months postburn. Brains were collected for analysis of key molecules expression, spleens for T cell function analysis, and blood for biochemistry and hormones detection. Results: Comparison with sham mice, burn mice showed extremely high locomotion in homecage, open field, and forced swimming tests, indicating a hyper-arousal state. Burn mice exhibited improved spatial memory in Morris Water Maze test and heightened context fear memory in context fear conditioning, suggesting re-experiencing behavior. Although burn mice showed pronounced passive avoidance in the step-through test, their active avoidance capability in response to the conditional stimulus in the shuttle box test was relatively deteriorated. Likewise, the retention of cue-feared memory was impaired in fear conditioning test. The above negative alterations in mood were recapitulated in open-field test, in which the burn mice displayed an anxiety-like behavior with less time spent in the center. However, no sign of depression was found in the forced swimming and sucrose preference tests. The negative mood of burn mice was reinforced by a deficit in sociality and preference for social novelty in social interaction test. These neurobehavioral alterations were associated with an increased expression of brain-derived neurotrophic factor along with a remarkable microgliosis and a moderate astrocytosis in the brain of burn vs. sham mice. Moreover, a prominent Th2 switch and consequent increased nuclear NF-kappa B translocation were seen in the splenic T cells from burn relative to sham mice. Conclusions: We conclude that even mild burn injury could lead to long-lasting cognitive and effective alterations in mice. These findings shed light on the interactions among neuropsychology, neurobiology, and immunology throughout the recovery period of burn injury.

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.

Objective To observe the infiltration of immune cells into the brain and the apoptosis of brain neurons after moderate burn injury. Method Thirty BALB/C male mice were randomly divided into two equal groups: burn group with their backs immersed in water at 94°C for 8s so as to cause second-degree burn in 15% of the total surface area (TBSA),and sham burn group with their backs immersed in water at 37℃..12 brains of mice from each group were removed after intracardiac normal saline perfusion 24 hours after scald.Mononuclear cells from the brain were isolated by discontinuous Percoll gradient centrifugation. For flow cytometry analysis, T cells were labeled with CD3+CD45high,monocytes with CD11b+CD45 high and activated microglia with CD11b+CD45int.The remaining 3 brains of each group were fixed and dehydrated.Then the frozen sections of brain tissue were stained by immunofluorescence for the immune cells,and with TUNEL method for the apoptotic cells.The sections were sealed with mounting medium for fluorescence with DAPI and photographed under confocal microscopy. Results The proportion of T cells in the brain tissue of burn group was[(1.103 ±0.674)%,significantly higher than that of the sham injury group[(0.385 ± 0.109)%,P<0.05]. The proportion of microglia(CD45intCD11b+)of the burn group was(1.017±0.35)%,significantly higher than that of the sham injury group [(0.502 ± 0.358)%,P<0.05],suggesting a higher degree of activation of microglia. Immunofluorescence staining showed an increased distribution of T cells and CD45high cells in the perivascular and choroid plexus of the burn group, compared with the sham injury group. Moreover, more apoptotic neurons were observed in the cerebral cortex and periventricular parenchyma of the brain in the burn mice relative to the sham injury mice. Conclusion As soon as 24 hours after moderate burn,infiltration of peripheral T cells and increasing number of apoptotic neurons can be observed in the brain, which may contribute to the following neuropsychiatric disorders.

Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury.

肠促胰素是一种肠道分泌的降血糖激素,可作用于胰岛β细胞促进胰岛素分泌,降低血糖. 胰高血糖素样肽-1 ( Glucagon-like peptide-1 , GLP-1 )是首先在小肠黏膜L细胞发现的一种肠促胰素,在进食等血糖升高情况下其释放增加. 由于GLP-1的血糖依赖性降血糖特性,糖尿病患者服用后不易发生低血糖事件,因此作为一种新型降血糖药物GLP-1 类胰泌素在临床得到广泛应用[1]. 天然 GLP-1 在体内极易被二肽基肽酶Ⅳ( Dipeptidyl peptidase Ⅳ, DPP-Ⅳ)广泛快速降解,临床上主要使用GLP-1 受体( GLP-1 receptor, GLP-1R )激动剂 Exendin-4 和DPP-Ⅳ活性抑制剂 Liraglutide. 近几年研究发现, GLP-1除具有降血糖作用外,还有心血管保护、神经保护和免疫调节作用,其强大的免疫功能一方面有利于对糖尿病的治疗,另一方面可能引起一定的副作用. 本文重点阐述 GLP-1 的免疫功能及其调节机制,为扩展肠促胰素类药物的临床应用范围,以及规避其免疫学风险方面提供了一定的参考.

在生理或病理状态下,免疫系统与中枢神经系统之间都存在着密切的交流.多种免疫细胞及其相关细胞因子可通过某些途径进入大脑,对神经细胞产生多种神经生物学作用,进而引起认知、情感、社会行为等多个方面的神经行为学改变.本文回顾了几种重要的免疫细胞及细胞因子对神经行为学的影响,阐明其神经免疫学机制,为预防急慢性炎症性疾病导致的神经行为学异常提供预警.