Brown Maria A, Jones W Keith
Department of Pharmacology and Cell Biophysics, 231 Albert Sabin Way ML0575, University of Cincinnati, Cincinnati, OH 45267-0575, USA.
Front Biosci. 2004 May 1;9:1201-17. doi: 10.2741/1304.
Sepsis is the clinical syndrome that results from a host's inflammatory response to infection via activation of the innate immune system. This response involves a complex network of inflammatory mediators that is self-reinforcing. When this immune response progresses uncontrollably, it can ultimately result in cardiovascular collapse and death. This complex inflammatory response is comprised of multiple mediators including cytokines such as TNF-alpha and IL-1beta, that are synthesized and secreted in response to signaling by receptors of the Toll-like receptor (TLR) family of pattern recognition receptors (PRR) that bind to pathogen associated molecules. A central downstream element of TLR-dependent signaling is the pleiotropic transcription factor NF-kappaB. NF-kappaB has been implicated in the regulation of multiple biological phenomena and disease states, including apoptosis, cell growth, stress response, innate immunity and septic shock. NF-kappaB-dependent genes are numerous and several have been implicated in the pathogenesis of sepsis and associated with cardiac dysfunction in sepsis. NF-kappaB activation occurs in multiple organs and cell types, and may be primarily protective in one tissue but injurious in another. Thus, a detailed understanding of the molecular basis of the pathophysiology of sepsis is needed in order to specifically block pro-inflammatory and pro-apoptotic signaling in the heart, while avoiding adverse effects in other organs.
脓毒症是宿主通过激活先天性免疫系统对感染产生炎症反应所导致的临床综合征。这种反应涉及一个自我强化的复杂炎症介质网络。当这种免疫反应不受控制地进展时，最终可能导致心血管衰竭和死亡。这种复杂的炎症反应由多种介质组成，包括细胞因子，如肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β），它们是在模式识别受体（PRR）的Toll样受体（TLR）家族的受体发出信号后合成并分泌的，这些受体与病原体相关分子结合。TLR依赖性信号传导的一个核心下游元件是多效性转录因子核因子-κB（NF-κB）。NF-κB与多种生物学现象和疾病状态的调节有关，包括细胞凋亡、细胞生长、应激反应、先天性免疫和脓毒性休克。NF-κB依赖性基因众多，其中一些与脓毒症的发病机制有关，并与脓毒症中的心脏功能障碍相关。NF-κB激活发生在多个器官和细胞类型中，在一个组织中可能主要起保护作用，但在另一个组织中可能具有损伤作用。因此，需要详细了解脓毒症病理生理学的分子基础，以便特异性阻断心脏中的促炎和促凋亡信号传导，同时避免对其他器官产生不良影响。
