Bacterial products [lipopolysaccharide (LPS) with Gram-negative bacteria and toxins, superantigens or cell wall fragments with Gram-positive bacteria] are the main activators of the septic shock cascade. These molecules interact with monocytes, macrophages and endothelial cells to produce inflammatory cytokines [tumour necrosis factor (TNF) and interleukins 1 and 6], and may activate other harmful pathways such as the coagulation system, complement cascade and lipid mediators. As a therapeutic strategy, antibodies directed against LPS have been well studied, although, on the whole, the clinical results have been disappointing. Other possible interventions that have not yet been tested clinically include natural intracellular antibacterial proteins (e.g. bacterial permeability-increasing protein) and high density lipoprotein (responsible for detoxifying LPS in the body). The stimulation pathway of responsive cells by bacterial products is also another possible target for intervention. Compounds under investigation include soluble CD14 and antibodies directed against CD14 or LPS binding protein. Antibodies directed against the cytokines are another option. Anti-TNF antibodies are currently being investigated, but conclusive evidence of their activity is still lacking. Soluble receptors (e.g. interleukin-1 receptor antagonist, or soluble TNF receptor) are another possibility; one soluble TNF receptor is still undergoing clinical investigation.

译文

细菌产物 [具有革兰氏阴性细菌和毒素的脂多糖 (LPS),具有革兰氏阳性细菌的超抗原或细胞壁碎片] 是败血性休克级联的主要激活剂。这些分子与单核细胞,巨噬细胞和内皮细胞相互作用,产生炎性细胞因子 [肿瘤坏死因子 (TNF) 和白介素1和6],并可能激活其他有害途径,例如凝血系统,补体级联反应和脂质介质。作为一种治疗策略,针对LPS的抗体已经得到了很好的研究,尽管总的来说,临床结果令人失望。尚未进行临床测试的其他可能的干预措施包括天然细胞内抗菌蛋白 (例如细菌通透性增加蛋白) 和高密度脂蛋白 (负责体内LPS的解毒)。细菌产物对应答细胞的刺激途径也是另一个可能的干预目标。正在研究的化合物包括可溶性CD14和针对CD14或LPS结合蛋白的抗体。针对细胞因子的抗体是另一种选择。目前正在研究抗TNF抗体,但仍缺乏其活性的确凿证据。可溶性受体 (例如interleukin-1受体拮抗剂或可溶性TNF受体) 是另一种可能性; 一种可溶性TNF受体仍在进行临床研究。

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