Clark Ian A, Budd Alison C, Alleva Lisa M
School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australia.
Malar J. 2008 Oct 14;7:208. doi: 10.1186/1475-2875-7-208.
Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines--generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbalpha) that control circadian rhythm--becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases.
严重全身炎症综合征的某些独特成分现已被充分认识到在疟疾、败血症、病毒感染和创伤后疾病中很常见。虽然它们与细胞因子的联系已被认识一段时间了，但构成该综合征的一系列变化一直被简单地视为一种经验观察，没有理论来解释它们为何会同时存在。关于主要促炎细胞因子对疾病行为基因控制影响的新数据可以扩展，以解释为什么该综合征包含许多常见成分，如可逆性脑病、基因沉默、红细胞生成异常、癫痫发作、凝血病、低白蛋白血症和高甘油三酯血症。因此有人提出，当促炎细胞因子通常具有的一种有利作用——通过适度抑制控制昼夜节律的基因（Dbp、Tef、Hlf、Per1、Per2和Per3以及核受体Rev-erbalpha）来产生疾病行为——变得过度时，就会出现构成全身炎症综合征大部分病理特征的模式。虽然可逆性脑病和基因沉默是严重事件，可能产生致命后果，但它们可被视为通过降低能量需求而具有生存优势。相比之下，红细胞生成异常、癫痫发作、凝血病、低白蛋白血症和高甘油三酯血症最好被视为当导致疾病行为的促炎细胞因子过度产生时，这些相同基因控制受到极端抑制的不幸后果。除了为全身炎症性疾病这些方面以前无法解释的共存提供新的解释外，这一概念与炎症细胞因子在这一系列疾病发病机制中起主要作用的观点是一致的。
