Septic shock cytokines

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E7. Endo, S., Inada, K., Inoue, Y., Kuwata, Y Suzuki, M., Yamashita, H., Hoshi, S and Yoshida, M T vo types of septic shock classified by the plasma levels of cytokines and endotoxin. Circ. Shock 38,264-274(1992). 

E8. Endo, S Inada, K., Nakae, H., Arakawa, N Takakuwa, T., Yamada, Y., Shimamura, T., Suzuki, M., Taniguchi, S and Yoshida, M., Nitrite/nitrate oxide (NOc) and cytokine levels in patients with septic shock. Res. Commun. Mol. Pathol. Pharmacol. 91,347-356 (1996). 

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Ultimately, the macrophages die, releasing the enormous built-up stores of TNF and cytokines, triggering a septic shock-like collapse of multiple organ systems. 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

Lysophosphatidylcholine protects mice in the lipopolysacharide-induced septic shock.11 The fact that the lipopolysacharide increases the concentration of cytokines (the same effect is observed upon the epidermal barrier disruption), and that lysophosphatidylcholine normalizes the cytokines level, provides the theoretical basis for treating disorders of the skin. 

Keywords Sepsis Septic shock Endotoxin Lipopolysaccharide Lipopolyamine Alkylpolyamine Polymyxin B Pharmacokinetics Pharmacodynamics Cytokine p38MAPK Prodrug... 

In the murine model of septic shock, DS-96 afforded significantly better protection than PMB at 4 mg/kg (p<0.01, Ch-square test (see manuscript)) (Fig. 12.18a). We confirmed that the protection afforded by DS-96 was attributable to attenuated LPS-induced cytokine production. DS-96 was without any effect on lethality induced by 100 ng/animal of recombinant murine TNF-a. Furthermore, an in vivo Schild-type profile was observed with multiples of LD100 doses of LPS requiring escalating doses of DS-96 for protection which clearly show the specificity of the compound as an LPS-sequestrant (Fig. 12.18b). In time-course experiments, DS-96 was maximally effective when administered concurrent to, or up to 4 h prior to LPS administration, partial protection persisted even up to 8 h prior to LPS challenge implying a favorable half-life (Fig. 12.19). This has been confirmed by pharmacokinetic (PK) experiments (see below). 

Dinarello, C.A. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J Infect Dis 163 (1991) 1177-1184. 

Dinarello, C.A. Cytokines as mediators in the pathogenesis of septic shock. Curr Top Microbiol Immunol 216 (1996) 133-165. 

NF-kB (nuclear factor kappa-light-chain-enhancer of activated B-cells) is a protein complex that acts as a transcription factor. It is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, UV radiation, oxidised lipoproteins and bacterial or viral antigens. It plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-/cB has been linked to cancer, inflammatory and automunune disease, septic shock, viral infection and improper immune development. 

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