The inflammatory cytokines. New developments in the pathophysiology and treatment of septic shock.

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.