发热

思考题,1. 发热时体温上升的基本环节。2. 体温升高是否可称为发热，为什么？3. 谈谈你对应用退热剂的看法。,发 热,fever,第一节 概述,温度感受器,视前区-下丘脑前部体温调节中枢(POAH),产热装置（骨骼肌、肝脏）,散热装置（汗腺、皮肤血管）,体温调节系统,体温,发热的相关概念,(Concepts of Fever),发热,体温上升 超过正常0.5度,？,体温升高,生理性体温升高,病理性体温升高,过热hyperthermia,发热fever,调节性体温升高,被动性体温升高,生理情况下，如运动，月经前期，妊娠均可使体温升高，特别是在剧烈运动时，体温可升高明显。,体温调节机构失调控或调节障碍：下丘脑退行性病变、广泛鱼鳞癣、广泛疤痕、先天性汗腺缺乏、中暑、甲亢等,体温调节中枢的调定点上移,(Causes and mechanisms of fever),第二节 病因和发病机制,发热激活物,产EP细胞（内生致热原）,EP,体温调定点上移,产热 散热,体温升高,一、发热激活物,(Pyrogenic activator),发热激活物的种类和性质,产内生致热原细胞,发热激活物的种类和性质,In vivoporcine lipopolysaccharide inflammation models to study immunomodulation of drugs,Lipopolysaccharide (LPS), a structural part of the outer membrane of Gram-negative bacteria, is one of the most effective stimulators of the immune system .To investigate the influence of these drugs on the clinical response, production of pro-inflammatory cytokines, acute phase proteins (APP) and the course of the febrile response in pigs,in vivoLPS inflammation models can be applied. Yet, to date,in vivo research on the immunomodulatory properties of antimicrobial drugs in these models in pigs is largely lacking. Numerous macrolide antibiotics are proven to decrease the production of TNF-, IL-1, IL-6 and PGE2both in humans and rodents.,Veterinary Immunology and Immunopathology 2015.8.15,A urinary metabonomics study on biochemical changes in yeast-induced pyrexia rats: A new approach to elucidating the biochemical basis of the febrile response Chemico-Biological Interactions, 2013,酵母是一种真菌,可以激活产内源性热原质（EP）细胞产生EP，作用于体温调节中枢，引起调定点的改变。本实验通过酵母诱导大鼠发热，用特定生化标志物标记来分析尿液的生化特性，发现色氨酸代谢受损可能是在发热反应的重要原因之一。,二、内生致热原,(Endogenous pyrogen ),（一）内生致热原的种类,The Role of Interleukin-6 in the Febrile Response, Linkping University Medical Dissertations,2013,We characterized for the first time the role of NF-IL6 for the development of LPS-induced sickness responses. We found that it influences immune-to-brain communication via the humoral and the cellular pathway and that it is involved in the maintenance and the termination of the febrile response reflecting natural programming of inflammation. We further showed that NF-IL6 may be implicated in the rhythm of HPA-axis-activity and the serotonin system and, thus, could be a potential therapeutic target for the treatment of brain inflammation and depressive disorders.,The transcription factor nuclear factor interleukin 6 mediates pro- and anti-inflammatory responses during LPS-induced systemic inflammation in mice,Brain, Behavior, and Immunity August 2015,(二) 内生致热原的生成和释放,(Production and release of endogenous pyrogen),产EP细胞的激活,LPS结合蛋白,一笑退热散对大鼠内毒素诱导发热模型退热机制的实验研究,动物模型建立：空白组腹腔注射 0. 9% 氯化钠注射液( 10 mL /kg) ，其余各组均腹腔注射 70 g /kg 的 LPS 建立大鼠发热模型,中药制备：造模后30 min 开始灌胃给药，模型组给予同体积生理盐水。,一笑退热散能有效抑制下丘脑 PGE2水平和降低血清中 TNF-、 IL-1 水平。所以一笑退热散的解热机制， 可能与其抑制内生致热源( EP) 如白细胞介素 IL-1、 TNF- 的致热作用和减少致热介质 PGE2 在中枢的合成与释放有关。 儿科药学杂志 2015 .02,Central mediators involved in the febrile response induced by polyinosinicpolycytidylic acid: Lack of involvement of endothelins and substance P,the aim of this study was to evaluate the participation of cytokines such as IL-1, TNF-, IL-6 and IFN- and of central mediators such asprostaglandins,endothelius opioidsand substance P in the febrile response induced by Poly I:C.,The present study showed for the first time that the Poly I:C-induced febrile response is, at least in part, dependent on the action of cytokines such as TNF- and IL-6 and INF- within the brain. In addition we showed that the febrile response induced by Poly I:C is also dependent on the synthesis and release of endogenous opioids but not on endothelin-1 and substance P. These results may be helpful to establish a model for a viral-induced febrile response that will enable us to study pathological mechanisms and search for new pharmacological targets.,Journal of Neuroimmunology 2015.1.15,三、发热时体温调节机制,(一) 体温调节中枢,(Thermoregulation center),正调节中枢负调节中枢,视前区-下丘脑前部 (preoptic anterior hypothalamus, POAH),发热激活物,体温,体温调定点,产EP细胞,EP,？,（二）致热信号传入中枢的途径,EP通过血脑屏障转运入脑EP通过终板血管器作用于体温调节中枢EP通过迷走神经向体温调节中枢传递发热信号 News in Physiological Sciences 1997,12:19,EP,巨噬细胞,巨噬细胞,POAH神经元,POAH神经元,第三脑室视上隐窝,视神经交叉,毛细血管,OVLT区,(三) 发热中枢调节介质,中枢发热正调节介质,前列腺素E (PGE)Na+/ Ca2+比值促肾上腺皮质激素释放激素 (CRH)环磷酸腺苷 (cAMP) 一氧化氮（NO）,Fever is a common response to inflammation and infection. The mechanism involves prostaglandin E2(PGE2)-EP3 receptor signaling in the hypothalamus, which raises the set point of hypothalamic thermostat for body temperature, but the lipid metabolic pathway for pyretic PGE2production remains unknown.To reveal the molecular basis of fever initiation, we examined lipopolysaccharides (LPS)-induced fever model in monoacylglycerol lipase (MGL)-deficient (Mgll/) mice.We findMGL is a critical enzyme for fever, which functions independently of endocannabinoid signals. MGL-dependent hydrolysis of endocannabinoid 2-arachidonoylglycerol is necessary for pyretic PGE2production in the hypothalamus.But hypothalamic PGE2caused by RANKL-RANK signaling in females may involve MGL-independent mechanism(s) in part, which awaits further studies.,Fever Is Mediated by Conversion of Endocannabinoid 2-Arachidonoylglycerol to Prostaglandin E2,PLOS ONE 2015.7.21,Glutathione deficiency attenuates endotoxic fever in rats,Glutathione constitutes the first line of the cellular defence mechanism against oxidative stress, and according to published data it is required by a number of factors that are involved in fever mechanism. The aim of the present study was to investigate whether or not glutathione deficiency can modulate a course of the fever induced by endotoxin (LPS).CONCLUSION: Based on these data, we conclude that glutathione deficiency modifies the LPS-induced fever, in a TNF- related manner. Int J Hyperthermia. 2015 Sep 14:1-7,(Pathophysiological basis of prevention and treatment for fever),第三节发热防治的病理生理基础,发热的利弊,有利方面进化论临床观察与动物实验机制研究有害方面增加能量消耗细胞变性影响胎儿发育使患者不适,Long-Lasting Impact of Early Life Immune Stress on Neuroimmune Functions Early life bacterial or viral infections can lead to a long-lasting impact on this natural febrile response. The early life pathogenic encounter heightens the hypothalamic-pituitary-adrenal axis response, dampens the innate immune system, and consequently reduces the febrile response to a subsequent immune challenge during adulthood。 早期细菌或病毒感染引起的自然发热加剧了下丘脑 - 垂体 - 肾上腺轴的活动，能挫伤先天免疫系统，降低成年期对发热反应的免疫能力。这种早期的“编程”效果，无论在产前或产后都将永久影响未来的神经免疫反应。 Medical Principles and Practice.2013.08,处理原则,治疗原发病一般处理补充水分、维生素及易消化营养物 及时解热体温过高、心脏病患者、妊娠妇女解热措施药物解热化学药物、类固醇、中草药物理降温,糖皮质激素的运用,发热病人中滥用激素的现象日益严重激素的滥用会改变原有的热型和临床表现延误诊断长期应用还将加重原有的感染性疾病或诱发二重感染等并发症延误必要的治疗,一般情况下不主张在病因未明的发热病人中使用激素,抗菌药物的使用,滥用抗生素治疗的直接后果是造成经济上的巨大浪费抗生素的使用将使细菌培养等病原学检查的阳性率大为下降长期应用多种抗生素导致药物热、二重感染等,疑为感染性发热且病情严重时，可在必要的实验室检查和各种培养标本采取后予经验性抗菌治疗。万古霉素-最后的王牌,目前临床医学中抗生素滥用的现象,无指证用药 ：临床医生通常会在诊断以及感染不明确的情况下就给患者使用广谱抗生素 ；患者和患者家属习惯性服用抗生素治病，而对于患者不合理的要求医生盲目迁就，甚至任意使用各种抗生素。联合用药不当：部分医生因自身专业知识欠缺而认为使用抗生素品种越多越好，多种抗生素联合使用虽然能够增加保险系数，但是却严重危害了患者的长远利益甚至会导致患者出现生命危险；而如果是同类的抗生素联合使用则会使药物的毒副作用增加。特殊患者：很多医生对特殊患者没有合理使用抗生素，对于新生儿、妊娠期患者、慢性肝、肾功能减退的患者不应该使用或者慎用抗生素等。 中国卫生标准管理 2015年第16期,258 例药品不良反应报告分析,由图可知：258 例 ADR 中，抗感染药物引起的 ADR居首位。,中国药物经济学 2015.7.15,全身中毒症状不甚明显,以淋巴瘤、恶性组织细胞病、白血病、肾上腺瘤、肝脏肿瘤及肠道肿瘤较常见,大多实体性肿瘤出现发热病程较晚，热度也较低 由于无明确的临床特点,较难与其他原因引起的发热区别开来，所以肿瘤性发热的诊断实际上就是一个排除性诊断。 2012,39(6):35535,肿瘤性发热：,原因不明发热（Fever of Unknown Origin，FUO）：,定义：指发热持续23周以上，体温几度超过38.5 ，经完整的病史询问、体格检查以及常规的实验室检查不能明确诊断者。,FUO 病因,感 染肿瘤性疾病结缔组织病最终诊断不明者, 80%,510%,国内外文献报道的 FUO 患者中以感染性疾病最常见，病种以上呼吸道感染、肺炎、胃肠炎和支气管炎居多，其次为无菌性炎症及恶性肿瘤。本文研究结果显示: 60例已确诊的患者中感染性疾病的患病率（ 69.5%）显著高于非感染性疾病（ 30.5%）。急诊 FUO 的病因以感染性疾病最多见，应尽早进行血培养检查；不能忽视感染性心内膜炎等特殊部位的感染和伤害等少见疾病造成的发热。重型结核和不典型结核是急诊 FUO 患者的结核病特征，可适时进行诊断性治疗。急 诊 FUO 患 者 中 非 感 染 性 疾 病 以风湿性疾病最常见,报道称大多 FUO 患者存在一定程度的心理障碍，表现为紧张、焦虑和恐惧，分析原因可能与检查频繁，症状无改善，住院时间长有关 。因此，在处理急诊 FUO 患者时应加强