Endotoxin blocking

More recently, other applications of CSLM in the characterization of membrane processes have been reported, such as the studies of Hayama et al. [26, 27] who visualized the distribution of an endotoxin trapped in an endotoxin-blocking filtration dialysis membrane. In their first study [26], they found that endotoxins were practically rejected by the outer skin layer of a polyester-polymer alloy (PEPA) membrane, hence playing a vital role in endotoxin removal from the dialysate fluid. In a second work [27], CSLM contributed successfully to visualize the distribution of endotoxin fiuorescently labeled in six kinds of dialysis membranes. They concluded that a dialysis membrane favorable for endotoxin blocking should have a double skin layer structure, composed of a hydrophilic inner skin layer and a completely hydrophobic void and outer skin layers. 

Hayama, M., Miyasaka, T., Mochizuki, S., Asahara, H., Yamamoto, K.-I., Kohori, R, Tsujioka, K., and Sakai, K. (2003). Optimum dialysis membrane for endotoxin blocking. J. Membr. Sci. 219, 15. Hemsley, D. A. (1989). Basic light microscopy and phase contrast microscopy. In D. A. Hemsley (Ed.), Applied Polymer Light Microscopy. Elsevier Science Publishers, Essex, England, p. 43. Hendra, P. J. (2005). Fourier transform Raman Spectroscopy. In J. J. Lasema (Ed.), Modern Techniques in Raman Spectroscopy. Wiley, Eastbourne, England, pp. 73-106. 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

Yang, F. et al., Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model, JNutr, 128, 2334, 1998. 

The ability of one stimulus to induce refractoriness to a second challenge with the same stimulus is called deactivation. This process appears to be specific for each stimulus Exposure of PMNs to FMLP diminished the formation of O and blocked the increase in the concentration of cAMP on second challenge with FMLP. However, both responses were elicited normally by C5,. The reverse was also true. Whether this phenomenon is due to internalization or occupancy of receptors for one stimulus while leaving intact those for the other is not known. The basis for the inhibitory effects of endotoxin on the responses of PMNs is unclear. For the inhibitory effects of phenothiazines see Transmission of Signal. ... 

Conceptually, the action of endotoxin could be blocked at several steps and trials studying different pathways have been (or are currently being) conducted. 

Bunnell, E., Lynn, M., Habet, K., Neumann, A., Perdomo, C.A., Friedhoff, L.T., Rogers, S.L. and Parrillo, J.E. A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia. Crit Care Med 28 (2000) 2713-2720. 

There seemed to be some hope of identifying such a receptor from the inside out. TNF, by this time taken as animportant endpoint of LPS responses, was synthesized as a result of separate transcriptional and translational activation events. Enhanced TNF gene transcription in myeloid cells followed LPS activation as a result of translocation of NF-/< B to the nucleus (40). Translational activation depended upon de-repression of a UA-rich element in the 3-untranslated region of the TNF mRNA (41). Subsequently, this event required activation of p38 (43), a protein that was first identified because it became phosphorylated in endotoxin-activated macrophages (44). In addition, LPS activated the MAP kinase pathway (45) and PI3 kinase pathway (46-49). The added importance of a tyrosine kinase in LPS signaling was suggested by the fact that tyrosine kinase inhibitors could block signal transduction (50). All attempts to find the critical transmembrane receptor that initiated these events were unsuccessful. 

Lipoxygenase Resistant to PAF-induced lethal shock Maintain sensitivity to endotoxin lethality Blocked production of leukotrienes... 

IL-1 acts on the brain to induce slow-wave sleep (and analgesia), which is not blocked by salicylates that prevent the concomitant fever (K30, TIO). In humans plasma IL-1 levels are higher during slow-wave sleep than in waking (M42). IL-1 is secreted by astrocytes in response to bacterial products, probably explaining the sleep-inducing effects of endotoxin and muramyl dipeptide (F23). 

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