Harmful molecular mechanisms in sepsis

Abstract

Sepsis is a systemic inflammatory response to severe infections, which eventually leads to tissue necrosis, multi-organ failure and death. In addition to its effects on the immune system, sepsis affects other biological systems such as the coagulation system and the autonomic nervous system. Through their amplification or suppression during sepsis, inflammatory mechanisms that are normally protective for the host can become instruments of harm. An overwhelming activation of the host pathogen-recognition system (in particular of Toll-like receptor 4) as a result of extensive tissue damage and/or severe infection initiates an excessive pro-inflammatory response in the early phase of sepsis, which leads to a severe imbalance of various body systems. The production of pro-inflammatory mediators is linked with pathophysiological mechanisms of inflammation in sepsis. The specific pleiotropic mediators that connect various pathways of the immune response can be considered 'central hubs' in the inflammatory network. These mediators include the complement anaphylatoxin C5a, macrophage migration-inhibitory factor (MIF), the pro-inflammatory mediator high-mobility group box 1 protein (HMGB1) and the cytokine interleukin-17A (IL-17A). Dysregulation of the coagulation cascade in sepsis results in severe complications, such as disseminated intravascular coagulation (DIC). Excessive activation of the complement system also has an important role in the pathogenesis of sepsis. It is now evident that the complement, coagulation and fibrinolysis systems interact in a complex network through multiple bidirectional connections. In sepsis, crosstalk between complement and coagulation pathways contributes to the pathogenesis of the disease. Inflammation is under the neuronal control of the autonomic nervous system, which can reflexively modulate the inflammatory response by inhibiting the production of pro-inflammatory cytokines and is therefore referred to as the 'inflammatory reflex'. The efferent arm of the inflammatory reflex, known as the cholinergic anti-inflammatory pathway, has been found to be important for suppressing cytokine production during sepsis. By contrast, the activation of adrenergic pathways in the early phase of sepsis promotes pro-inflammatory responses through direct effects on immune cells, which can synthesize neurotransmitters and their receptors. The pathology of sepsis involves a complex interplay between different biological systems that results in severe dysregulation of the inflammatory network. It is important to consider that sepsis is a heterogeneous, dynamic syndrome, and that successful treatment will require various treatment options that should be adjusted to an individual patient's situation.