Krueger J M, Majde J A
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163, USA.
Crit Rev Immunol. 1994;14(3-4):355-79. doi: 10.1615/critrevimmunol.v14.i3-4.70.
Excessive sleepiness and fever are constitutional symptoms associated with systemic infection. Although fevers have been investigated for many years, sleep responses to infectious challenge have only recently been investigated. Inoculation of animals with bacterial, viral, protozoan and fungal organisms result in complex sleep responses dependent upon the microbial agent and route of administration. The general pattern is characterized by an initial robust increase in non-rapid eye movement sleep (NREMS) followed by a period of NREMS inhibition. REMS is inhibited after infectious challenge. The sleep responses are accompanied by fever but the two responses are, in part, independent from each other. Sleep responses, like fevers, may be beneficial to host defense although this area is relatively uninvestigated. Microbial products likely responsible for sleep and fever responses include bacterial muramyl peptides and endotoxin, and viral double stranded RNA. These microbial products induce sleep and fever responses in animal models. The exact mechanism of how these structurally diverse microbial products elicit sleep and fever remain unknown; however these substances share the ability to induce cytokine production. Cytokines such as interleukin-1 (IL-1), tumor necrosis factor, acidic fibroblast growth factor (FGF), and interferon-alpha (IFN-alpha) are somnogenic whether given directly into brain or intravenously. Other cytokines lack somnogenic activity, e.g., IL-2, IL-6, IFN beta and basic FGF. The somnogenic actions of cytokines probably involve growth hormone-releasing hormone (GHRH) and nitric oxide. Anti-GHRH or inhibition of NO production inhibits normal sleep and inhibits IL-1-induced sleep. In conclusion, cytokines are likely key mediators of fever and sleep responses to infection. The microbial-cytokine altered sleep likely results from an amplification of physiological sleep mechanisms which include cytokines, several neuropeptides and neurotransmitters such as nitric oxide.
过度嗜睡和发热是与全身感染相关的全身症状。尽管发热已经被研究了很多年，但睡眠对感染刺激的反应直到最近才被研究。用细菌、病毒、原生动物和真菌生物体接种动物会导致复杂的睡眠反应，这取决于微生物制剂和给药途径。一般模式的特点是，非快速眼动睡眠（NREMS）最初会强劲增加，随后是NREMS抑制期。感染刺激后，快速眼动睡眠（REMS）会受到抑制。睡眠反应伴随着发热，但这两种反应在一定程度上相互独立。与发热一样，睡眠反应可能对宿主防御有益，尽管这方面的研究相对较少。可能导致睡眠和发热反应的微生物产物包括细菌胞壁酰肽和内毒素，以及病毒双链RNA。这些微生物产物在动物模型中诱导睡眠和发热反应。这些结构多样的微生物产物引发睡眠和发热的确切机制尚不清楚；然而，这些物质都具有诱导细胞因子产生的能力。细胞因子如白细胞介素-1（IL-1）、肿瘤坏死因子、酸性成纤维细胞生长因子（FGF）和干扰素-α（IFN-α），无论是直接注入大脑还是静脉注射，都具有诱导睡眠的作用。其他细胞因子缺乏诱导睡眠的活性，例如IL-2、IL-6、IFN-β和碱性FGF。细胞因子的诱导睡眠作用可能涉及生长激素释放激素（GHRH）和一氧化氮。抗GHRH或抑制一氧化氮的产生会抑制正常睡眠，并抑制IL-1诱导的睡眠。总之，细胞因子可能是感染引起发热和睡眠反应的关键介质。微生物-细胞因子改变睡眠可能是由于生理睡眠机制的放大，这些机制包括细胞因子、几种神经肽和神经递质，如一氧化氮。
