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Systemic inflammatory response syndrome

This syndrome is generally seen as a systemic expression of multiple inflammatory mediators (cytokines and cytokine signals that normally function in an autocrine, paracrine, or juxtacrine fashion together with oxygen free radicals, coagulation factors). Not only pro-inflammatory cytokines but also anti-inflammatory cytokines are elevated in the blood stream and the condition has been referred to as a "Cytokine storm" or, more scientifically) cytokinemia or hypercytokinemia (see also: cytokine release syndrome).

Sepsis (septic shock syndrome; abbr. SSS) is a systemic inflammatory response syndrome caused by an infection. It is a severe and frequently lethal hemodynamic break-down observed after Gram-negative septicemia and mainly caused by bacterial endotoxins.

The so-called toxic shock syndrome (abbr. TSS) observed mainly in younger women is caused by tampons contaminated with Staphylococcus aureus. These bacteria produce an exotoxin of 23.1 kDa, TSST-1 (toxic shock syndrome toxin-1), which induces the synthesis of IL1 and TNF. An essential role of CD28 costimulatory signals in TSST-1 induced toxic shock syndrome has been established by studies of transgenic mice deficient in expression of CD28.

Multiple organ dysfunction syndrome (abbr. MODS) may represent the end stage of severe systemic inflammatory response syndrome or sepsis. The symptoms are characterized by hypotension, insufficient tissue perfusion, uncontrollable bleeding, and multisystem organ failure caused mainly by hypoxia, tissue acidosis, and severe local alterations of metabolism. The massive deterioration of homeostasis, known also as disseminated intravasal coagulation, involves blood vessels, platelets, blood coagulation and fibrinolytic processes, the presence or absence of inhibitors, the kallikrein-kininogen system (see also: Kallikreins), and complement. Management of the shock-specific symptoms is still one of the most challenging problems faced by clinicians.

At the cellular level the shock syndrome is elicited by endogenous mediators. Although the list of shock mediators currently comprises more than 150 candidates a careful analysis reveals that only a few are causally associated with shock symptoms, including histamine, complement factor C5a, Beta-Endorphin, thromboxane B2, platelet activating factor, and oxygen free radicals. Plasma levels of Alpha-2-Macroglobulin, an inhibitor of different proteinases, have been described to be reduced in patients with sepsis and to be associated with fatal outcome in some studies. The major pro-inflammatory cytokines involved in septic shock are IL1, IL6 and TNF-alpha, which are released by macrophages following cell activation by bacterial endotoxins. Hemofiltration or hemoadsorption only partially remove these mediators from the circulation and the clinical significance of these procedures is still uncertain (Teraoka et al, 2000; Hoffmann and Faist, 2001).

IL1 causes tachycardia and hypotension. It synergises with TNF the activity of which is also potentiated by IFN-gamma. TNF mainly acts on endothelial cells and increases their procoagulatory activity. Activated endothelial cells also express a number of adhesion molecules that facilitate the adhesion of leukocytes to the endothelium. The accumulation of inflammatory cells further contributes to the tissue destruction (see also: inflammation).

Rabbits challenged with a lethal dose of endotoxins produce several milligrams of TNF per kg of body weight which quickly reaches all tissues by the blood circulation. The symptoms observed after administration of pure TNF are almost identical with those observed after an endotoxin shock (see also: Shwartzman phenomenon). The severe effects of an endotoxinemia can be abolished almost completely by administration of antibodies directed against TNF. The importance of TNF in shock is illustrated by studies of mice in which one of the TNF receptors has been deleted by homologous recombination (see TNF-alpha, subentry Transgenic /Knock-out/Antisense studies). TNF receptor deficient mice are resistant to endotoxic shock although they still succumb to infections with some other pathogens.

In humans TNF serum concentrations in excess of 1 ng/mL are frequently an indication of the lethal outcome of bacterial sepsis. However, absolute serum concentrations of cytokines involved in the pathophysiology of Septic shock are normally no reliable indicators of the severity of the shock state and also do not allow prediction of the clinical outcome.

A markedly enhanced activity of TNF is observed in hepatectomised mice and also in mice treated with hepatotoxins such as galactosamin. This may be due to a block of an endogenous feedback mechanism controlling toxic concentrations of TNF since the liver is the major site of IL6 synthesis, which in turn is responsible for the induction of the synthesis of acute phase proteins (see: acute phase reaction).

Monoclonal antibodies directed against bacterial endotoxins inactivate the bacterial toxin and therefore act the beginning of the causal chain of events. Such antibodies are of prophylactic value only and cannot be used to treat acute cases. Animal experiments with genetically engineered IL1 receptor antagonists (see: IL1ra) have shown that this substance positively influences blood pressure, initial leukopenia, and later leukocytosis in Septic shock. This antagonist can be used also at least 2 hours after administration of endotoxins. At this stage untreated animals already display the first symptoms of shock. Administration of endotoxins at doses that normally lead to the death of 8 out of 10 animals within 48 hours after administration nine out of ten animals survive if the receptor antagonist is given at the same time as the endotoxins.

While untreated animals show severe destruction of lung architecture characterized by edemas of the alveolar walls and massive infiltration of blood cells, animals treated with the receptor antagonist and surviving the administration of endotoxins only display small focal bleeding. They usually recover completely within a week.

Unfortunately the IL1 receptor antagonist has a very short plasma half-life and therefore optimal effects are obtained only at relatively high doses on the order of approximately 100 mg/kg body weight. Work is currently in progress to genetically engineer this factor to obtain variants with higher specific activity and improved biological half-lives. For other drug treatments involving substances that inhibit cytokine synthesis see, for example: Pentoxifylline.

Copyright 2012 by H IBELGAUFTS. All rights reserved.


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