Septic Shock
Septic shock is the most severe complication of sepsis with a high mortality rate despite that potent antibiotics and improved intensive care are provided in present days. Sepsis is defined as infection with evidence of systemic inflammation, consisting of two or more of the following: increased or decreased temperature or leucocyte count, tachycardia, and rapid breathing.
Septic shock is sepsis with hypotension that persists after resuscitation with intravenous fluid. This disease commonly originates from certain local infections such as abdominal or digestive system infections, lung infections like pneumonia, urinary tract infection and reproductive system infection. Under normal circumstances, the local inflammatory process is strictly controlled by the immune and neuroendocrine system for eradicating the invading pathogens. However if the local inflammation loses out of control, the systemic inflammation may occur and further develop into sepsis, severe sepsis or septic shock.
The Involvement of Complement in Septic Shock
Various factors have an impact on the initiation of the complement cascade during the process of sepsis. Recently published data from human studies have indicated that Gram-positive and Gram-negative bacteria can initiate the complement activation in distinct ways. Gram-positive pathogens in sepsis mainly lead activation of the classical pathway of complement in which the protein C1q binds directly to the surface of bacteria or to immune complexes formed by bacteria antigens and antibodies. In the case of Gram-negative pathogens, the binding of MBL predominantly to the LPS of Gram-negative bacteria’s wall activates the lectin pathway of complement.
The initiation of complement can directly lead to the cleavage of C3 and C5, the most two core proteins of this process. It has been reported that the activated C3 fragments, C3a and C3b/c, were increased in septic shock patient which is thought to be correlated with mortality. Other basic and clinical findings indicated that anaphylatoxins C3a may be an essential element in recruiting inflammatory cells to combat infections whereas excessive release of these factors could be detrimental.
Therapeutic Strategies for Septic Shock
The current clinical management for septic shock typically involves the following aspects: early identification and treatment of causative infection, adequate and rapid hemodynamic resuscitation, treatment of organ failure, corticosteroids, and regulation of the immune response. Certain strategies now directly target key proteins of the complement cascade such as anti-C5a agents or C5aR -blockers, administration of C1-INH for blocking complement activation, or indirectly strategies affect complement system like anti-TNF treatment. Direct or indirect inhibition of complement both could provide new approaches for the treatment of septic shock. Given the invaluable role of C3 in the development of septic shock, it may have the potential to be another specific and effective targeting strategies.
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Questions & Answer
A: Experimental studies have shown that complement inhibitors can reduce the severity of septic shock in animal models. These inhibitors can mitigate inflammation, organ dysfunction, and mortality. Clinical trials are also ongoing to further evaluate the safety and efficacy of complement-targeted therapies in humans.
A: Experimental models use various approaches, such as lipopolysaccharide injection, cecal ligation and puncture, or live bacterial inoculation in animals, to induce septic shock. These models aim to mimic key aspects of human sepsis, including systemic inflammation, organ dysfunction, and mortality.
A: Future research may focus on the development of more specific and targeted complement inhibitors. Additionally, studies might explore the use of combination therapies that integrate complement modulation with other sepsis treatments to further improve outcomes. A comprehensive understanding of the complement system's role in septic shock will continue to drive experimental research in this field.
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