Which of the following statement(s) is/are true concerning tumor necrosis factor (TNF)? a. TNF is a product of activated macrophages secreted in response to contact with endotoxin or lipopolysaccharide, antibody complexes, or inflammatory stimuli b. The liver and gut appear to be a major source of TNF following hypoperfusion c. Circulating levels of TNF correlate well with severity of tissue injury in shock d. Recently completed clinical trials of anti-TNF antibody in septic patients shows a marked improvement in survival

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Answer: a, b  Tumor necrosis factor (TNF), a protein product of activated macrophages, is secreted in response to contact with endotoxin or lipopolysaccharide, antibody complexes, or other inflammatory stimuli. Elevation of serum levels of TNF have been reported shortly after experimental trauma and shock, however, documentation of elevated circulating levels of TNF in human shock is less clear. Furthermore, circulating levels of TNF cannot be correlated with severity of tissue injury or shock. This variability is thought to be due to rapid clearance and uptake by membrane receptors and by soluble membrane receptors that are released from multiple cells following stress and injury. Following hypoperfusion the liver and gut appear to be the major source of TNF that is rapidly cleared but responsible for inducing hepatocyte changes following shock. The release of breakdown products and escape of bacterial and endotoxin through the damaged mucosal barrier of the gut following shock allows or induces activation of tissue-fixed macrophage (Kupffer cell) of the liver which then produces secondary inflammatory mediators contributing to the post-resuscitation clinical response and inflammatory mediator activation seen in the systemic inflammatory response syndrome. TNF is central to inflammatory response, particularly in sepsis and following endotoxemia or bacteremia. TNF also induces secondary inflammatory responses through direct interaction with specific membrane receptors, TNF-r. Treatment with anti-TNF antibody in the experimental setting protects animals from the deleterious effects of lethal bacteremia and endotoxemia. However, recently completed clinical trials in septic patients utilizing infusion of monoclonal antibodies to the TNF molecule have shown no overall survival benefit

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