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  • Review Article
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Harmful molecular mechanisms in sepsis

Key Points

  • 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.

Abstract

Sepsis and sepsis-associated multi-organ failure are major challenges for scientists and clinicians and are a tremendous burden for health-care systems. Despite extensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. We are now beginning to understand that sepsis is a heterogeneous, dynamic syndrome caused by imbalances in the 'inflammatory network'. In this Review, we highlight recent insights into the molecular interactions that occur during sepsis and attempt to unravel the nature of the dysregulated immune response during sepsis.

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Figure 1: Central hubs of the inflammatory response in sepsis.
Figure 2: C5a is a central mediator of the inflammatory response in sepsis.
Figure 3: Cross-talk between the complement, coagulation and fibrinolysis systems.
Figure 4: Effects of pathways of the ANS on inflammation during sepsis.
Figure 5: The inflammatory network in sepsis.

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Acknowledgements

This work was supported by grants GM-29,507, HL-31963 and GM-61656 from the National Institutes of Health, USA, to P.A.W.

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Glossary

Sepsis

A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Nosocomial infections

These are infections that occur during treatment in a hospital or a healthcare service unit and are secondary to the patient's original condition. Nosocomial stems from the Greek word 'nosokomeion' meaning hospital ('nosos', disease; 'komeo', to take care of). This type of infection is also known as a hospital-acquired infection.

Anaphylatoxin

The pro-inflammatory complement-activation fragments C3a, C4a and C5a are also known as anaphylatoxins. They mediate inflammatory responses through cell activation and induce effects such as chemotaxis and histamine release.

Neutrophil extracellular traps

(NETs). A set of extracellular fibres produced by activated neutrophils to ensnare invading microorganisms. NETs enhance neutrophil killing of extracellular pathogens while minimizing damage to host cells.

Tautomerase activity

The ability to catalyse the tautomerization (switching from one isomeric form to another) of D-dopachrome and L-dopachrome methyl ester into their corresponding indole derivates. This reaction was used by early life forms for synthetic pathways. Macrophage migration-inhibitory factor (MIF) has been shown to have tautomerase activity; this evolutionarily conserved catalytic function is responsible for its pro-inflammatory effects.

Cholinergic anti-inflammatory pathway

This pathway fine-tunes cytokine production during inflammation in a highly regulated and reflexive manner. Interaction of acetylcholine with the α7-nicotinic acetylcholine receptor (α7nAChR) expressed by macrophages results in the suppression of pro-inflammatory cytokine production. The main component of this pathway is the vagus nerve of the parasympathetic branch of the autonomic nervous system.

Endotoxaemia

This is caused by the presence of endotoxins, which are derived from Gram-negative bacteria, in the blood. It results in systemic activation of the inflammatory response, the development of shock and multi-organ failure and death. Models of endotoxaemia are used in experimental settings to induce systemic inflammation, but they do not necessarily mimic human sepsis.

Septic cardiomyopathy

The decreased myocardial function that occurs during sepsis-associated multi-organ failure. Hypotheses concerning the aetiology of this decreased function include impairment of mitochondrial function, dysfunction of the β-adrenoceptor–G-protein–adenylate cyclase system, calcium-channel blockade by direct and indirect cardiodepressant factors and contractile impairment by activated leukocytes.

Disseminated intravascular coagulation

(DIC). Also known as consumptive coagulopathy, this is a pathological process in which the blood begins to coagulate throughout the entire body. During this process, platelets and coagulation factors are depleted, resulting in a paradoxical situation in which there is a high risk of simultaneous fatal thrombosis and large-scale haemorrhage. DIC often occurs in critically ill patients with overwhelming infection, fulminant sepsis or malignancy.

Thrombin

Thrombin (also known as activated Factor II) is the central serine protease that converts soluble fibrinogen into insoluble strands of fibrin. It also catalyses many other coagulation-related reactions.

Tissue factor

A pro-coagulant factor that stimulates thrombus formation following contact with blood by accelerating the action of the coagulation factors Factor VIIa and Factor Xa. It can also be expressed on the surface of activated endothelial cells.

Activated protein C

A physiological anticoagulant. The activated form degrades Factor Va and Factor VIIIa of the coagulation cascade. The protein-C pathway has anti-thrombotic activity, as well as anti-inflammatory and anti-apoptotic functions. Administration of human recombinant activated protein C for the treatment of sepsis might block dysregulated coagulation, inhibit pro-inflammatory pathways and preserve organ function.

Thrombomodulin

An integral membrane protein that is expressed on the surface of endothelial cells. It functions as a co-factor in thrombin-induced activation of protein C in the anticoagulant pathway by forming complexes with thrombin. Thrombomodulin–thrombin complexes also stimulate fibrinolysis by cleaving thrombin-activatable fibrinolysis inhibitor (TAFI) into its active form.

Catecholamines

Tyrosine-derived mediators that are produced mainly by the adrenal medulla and by the postganglionic fibres of the sympathetic nervous system. Recently, it has been found that immune cells are also a source of catecholamines. The most abundant catecholamines are the biogenic amines adrenaline, noradrenaline and dopamine, which function as neurotransmitters in the sympathetic branch of the autonomic nervous system through interaction with adrenergic receptors expressed by numerous cell and tissue types.

Kupffer cells

The resident macrophages of the liver, which are derived from blood monocytes. They phagocytose pathogenic particles and microorganisms that have entered the liver sinusoids.

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Rittirsch, D., Flierl, M. & Ward, P. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8, 776–787 (2008). https://doi.org/10.1038/nri2402

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