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. Author manuscript; available in PMC: 2009 Dec 2.
Published in final edited form as: Nat Rev Immunol. 2008 Oct;8(10):776–787. doi: 10.1038/nri2402

Figure 5. The inflammatory network in sepsis.

Figure 5

During sepsis, homeostasis between the various biological systems of the inflammatory network is highly imbalanced. In the initiation of sepsis, the release of a large amount of damage-associated molecular patterns (DAMPs) from invading microorganisms and/or damaged host tissue results in the overstimulation of pattern-recognition receptors (PRRs) on immune cells. Activated immune cells release excessive amounts of pro-inflammatory mediators (resulting in a ‘cytokine storm’), free radicals and enzymes, which converts the normally beneficial effects of inflammation into an excessive response that damages the host. Activation of the adrenergic branch of the autonomic nervous system (ANS) and/or decreased activity of the cholinergic anti-inflammatory pathway (of the parasympathetic branch of the ANS) further amplifies the pro-inflammatory responses of neutrophils, macrophages and dendritic cells in sepsis. The presence of invading microorganisms or their products in the blood can cause systemic activation of the complement system, which results in the excessive generation of complement anaphylatoxins, which, at high concentrations, induce numerous harmful effects. Simultaneous activation of the coagulation system and the inhibition of fibrinolysis as a result of the pro-inflammatory environment and/or damaged endothelium can result in disseminated intravascular coagulation (DIC), which is a major complication of sepsis, and in the amplification of the inflammatory response. The complement, coagulation and fibrinolysis systems are tightly connected through direct interactions of serine proteases, and imbalances in each cascade are intensified in a positive-feedback loop (FIG. 4). Finally, the sustained pro-inflammatory environment affects the functional state of immune effector cells, eventually causing the dysfunction of neutrophils and immunoparalysis. Alterations in leukocyte apoptosis in the later stages of sepsis further account for immunosuppression, which increases the susceptibility to secondary infections.