Sepsis – the most common cause of death in hospitalized patients – affects over 18 million people worldwide and has an expected 1% increase of incidence per year. Recent clinical trials indicate that therapeutic approaches effective in diseases with similar pathogenesis have a modest effect against sepsis. Future clinical trials might define patient populations and therapeutic strategies according to the profile of expression of cytokines.(figure1)
Infection, trauma, ischemia and severe injury contribute to the pathogenesis of severe sepsis, which is characterized by an overwhelming production of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1b and high-mobility group box (HMGB)-1. These cytokines trigger a beneficial inflammatory response that promotes local coagulation to confine tissue damage. However, the excessive production of these proinflammatory cytokines can be even more dangerous than the original stimulus, overcoming the normal regulation of the immune response and producing pathological inflammatory disorders.
Sepsis also activates the production and release of specific ant-inflammatory substances, including the cytokine receptor antagonists, the soluble sytokine receptors and the anti-inflammatory cytokines. Interleutin-1 receptor antagonist(IL-1Ra) is a naturally occurring inhibitor of Il-1, which competitively binds to the IL-1 receptor and inhibits the actions of IL-1. Interleukin-10(IL-10) is an anti-inflammatory cytokine, which probably has an important down-regulatory function in decreasing the production of various proinflammatory cytokines, such as TNF-α,IL-1β,IL-6 and IL-8. Theoretically, these anti-inflammatory substances may have an important regulatory function in controlling and attenuating the systemic inflammatory response in sepsis.
This is especially notable in severe sepsis, in which the excessive production of proinflammatory cytokines causes capillary leakage, tissue injury and lethal organ failure. Experimental strategies neutralizing these cytokines (monoclonal antibodies against TNF, IL-1-receptor antagonists and TNF-receptor fusion proteins) are a successful therapeutic approach against several inflammatory disorders, including rheumatoid arthritis and Crohn's disease. However, these cytokine-based strategies have produced modest effects in clinical trials and failed to receive the approval of the Food and Drug Administration (FDA) in the US for the treatment of sepsis. Therapeutic approaches that appear effective in diseases with similar pathogenesis have failed against sepsis.
TNF is a sufficient and necessary mediator of septic shock because: (i) it is found in patients and experimental models of septic shock; (ii) it is capable of triggering the entire spectrum of hemodynamic, metabolic and pathological sequelae of septic shock. The administration of TNF causes shock, hypotension, intravascular coagulopathy and the characteristic hemorrhagic necrosis and tissue injury observed in septic shock; and (iii) the neutralization of TNF prevents endotoxic- or bacteremic-induced shock, even when endotoxins or bacteria persist in the circulation.
Neutralizing antibodies against TNF are successful therapeutic strategies against rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis, but they have produced only modest results against sepsis. A possible explanation is that some patients enrolled in these clinical trials suffer from severe sepsis, and TNF appears to be a mediator of septic shock but not of severe sepsis. Unlike chronic inflammatory disorders, sepsis is characterized by a sequential pattern of cytokine expression. TNF is secreted within minutes after infection, but after 3–4 h secretion stops and serum TNF levels become almost undetectable. Thus, anti-TNF therapy provides a narrow therapeutic time frame for clinical intervention in acute infection or trauma, because it is ineffective when administered after the acute expression of the cytokine.
Originally described as a nuclear DNA-binding protein, HMGB1 can also be secreted into the extracellular milieu by stimulated macrophage, and extracellular HMGB1 functions as a proinflammatory cytokine that contributes to severe sepsis.
HMGB1 seems to be a sufficient and necessary mediator for severe sepsis because: (i) systemic HMGB1 is found in patients and experimental models of sepsis-induced organ dysfunction defined for severe sepsis; (ii) the admin-istration of recombinant HMGB1 to mice recapitulates the characteristic organ dysfunction of severe sepsis, includ-ing derangement of the intestinal barrier function, acute lung injury and lethal multiple organ failure; and (iii) the inhibition of HMGB1 secretion or activity prevents endotoxin- or bacteremia-induced multiple organ failure. HMGB1 is defined as a late mediator of sepsis because macrophages secrete HMGB1 ~20 h after activation and serum HMGB1 is detected in a prolonged plateau beginning 20–72 h after disease onset. By contrast, early cytokines, such as TNF and IL-1, are produced within minutes of stimulation and their circulating levels typically revert to near-baseline levels within the first few hours during the progression of the disease. Unlike early cytokines, HMGB1 is a late mediator sepsis that might be a potential therapeutic target to treat 'established' sepsis.
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