Cytokines in the systemic inflammatory response syndrome: a review

Abstract

Introduction: Patients subject to major surgery, suffering sepsis, major trauma, or following cardiopulmonary bypass exhibit a systemic inflammatory response. This inflammatory response involves a complex array of inflammatory polypeptide molecules known as cytokines. It is well accepted that the loss of local control of the release of these cytokines leads to systemic inflammation and potentially deleterious consequences including the Systemic Inflammatory Response Syndrome, Multi-Organ Dysfunction Syndrome, shock and death.

Methods: The Medline database was searched for literature on mechanisms involved in the development of SIRS and potential targets for modifying the inflammatory response. We focus on the novel therapy of cytokine adsorption as a promising removal technology.

Results: Accumulating data from human studies and experimental animal models suggests that both pro- and anti- inflammatory cytokines are released following a variety of initiating stimuli including endotoxin release, complement activation, ischaemia reperfusion injury and others.

Discussion: Pro-and anti-inflammatory cytokines interact in a complex and unpredictable manner to influence the immune system and eventually cause multiple end organ effects. Cytokine adsorption therapy provides a potential solution to improving outcomes following Systemic Inflammatory Response Syndrome.

Keywords: SIRS; cytokine; inflammatory response; syndrome; systemic.

Figure 1

Initiators of SIRS. - LPS “Endotoxin” is a component of gram-negative bacterial cell walls and is continuously sheared off into surrounding interstitial fluid and serum. LPS degrades into the O-antigen and Core protein, which have little immunogenic effect and Lipid-A which is highly pro-inflammatory. Lipid-A binds the CD14/TLR4/MD2 receptor on monocytes and tissue macrophages to trigger the NF-κβ protein family. This messenger translocates to the cell nucleus and initiates the production of pro-inflammatory cytokines via primer binding. - TNF binds the TNF-R (types 1 and 2) to trigger three main intracellular pathways; the FADD, the TRAF-ASK1 and TRAF2-RIP pathways. These proteins activate intracellular caspase enzymes which degrade DNA by proteolysis and induce changes in DNA expression, thus cellular function and cause apoptosis. Dyscytokinaemia can results in uncontrolled cell death and organ dysfunction. - Direct cell plasma membrane trauma results in the production of ecosanoids by PLA2 and the COX family (as well as other mediators). Prostaglandins affect tissue perfusion by controlling vasoconstriction/dilation and platelet aggregation. Leukotrines control vessel permeability as well as stimulating inflammatory cell chemotaxis. Lipoxins control cell adhesion and migration. Dysregulation of these mediators results in ishaemia/hyperaemia and tissue damage. - Complement cascade activation (via the classic or alternative pathway) results in the production of the membrane attack complex (C5b6789) which perforates the plasma membrane of the call on which it is formed. Formation can occur on any cell, but most commonly on bacteria, resulting in lysis and dissemination of bacterial antigens (eg. LPS). Normal cells express protectin on their surface, which prevent lysis by the membrane attack complex, however, uncontrolled activation of complement and production of this enzyme can overcome this protection and result in autolysis. Deficiences can also result in severe disseminated infection. - Anaphylaxis is an acute systemic type 1 hypersentivity reaction to an innocuous antigen. The resulting massive histamine release causes profound vasodilation, recruitment of inflammatory cells and the subsequent production of pro-inflammatory cytokines. If this process continues, it can result in tissue hypoxia and organ dysfunction. - DIC results from uncontrolled activation of the clotting cascade by pro-inflammatory mediators. As a result, haemorrhage occurs throughout the body (micro/macro) and results in further tissue damage, hypoxia and pro-inflammatory cytokine results. Organ dysfunction can develop rapidly. - Ischaemia-Reperfusion injury occurs when a tissue has been hypoxic for a prolonged period and produces large quantities of pro-inflammatory & vasodilating mediators. When the tissue is reperfused, the effect is local hyperaemia and restuling tissue damage and the release of potent concentrations of cytokines into the systemic circulation. Reactive hyperaemia can induce rapid production of vasoconsricting mediators, leading to capillary level dysfunction. This cycle of ischaemia and hyperaemia leads onto tissue damage and further pro-inflammatory cytokine production. CD = cluster of differentiation, TLR = Toll-like receptor (TLR4 aka. CD284), MD2 = lymphocyte antigen 96 (aka. LY96), MAP = mitogen activated phosphokinases, ERK = extracellular signal-regulated kinases, JNK = c-Jun N-terminal kinases, DIC = Disseminated Intravascular Coagulation

Figure 2

Balance between pro- and anti-inflammatory cytokines.

Figure 3

Mechanism of Lipopolysaccharide (LPS) “Endotoxin” pathogenesis. Gram negative bacteria have a lipopolysaccharide (LPS) membrane outside the peptidoglycan layer. 1. LPS (“endotoxin”) is sheared from the bacterial membrane continuously into surrounding interstitial fluid and serum. 2. LPS degrades into the O-antigen and Core protein which have little immunogenic effect and Lipid-A which is highly pro-inflammatory. 3. Lipid-A binds the CD14/TLR4/MD2 receptor of tissue macrophages and serum monocytes to trigger intracellular pathways. 4. The NF-κβ protein family is activated via a complex multiple step intracellular process, which translocates to the nucleus and initiates production of pro-inflammatory cytokines. 5. This results in a mass release of pro-inflammatory cytokines including TNFα and IL-12 CD = cluster of differentiation, TLR = Toll-like receptor (TLR4 aka. CD284), MD2 = lymphocyte antigen 96 (aka. LY96), MAP = mitogen activated phosphokinases, ERK = extracellular signal-regulated kinases, JNK = c-Jun N-terminal kinases

Figure 4

The cellular affects of TNFα. Tumour Necrosis Factor alpha (TNFα) is produced by macrophages, lymphocytes, fibroblasts and keratinocyte. TNFα binds the TNF receptors (TNF-R/CD120a/CD120b). There are 2 types of TNF-R; - TNF-R type 1 (CD120a) - present on all cells and binds TNFα only - TNF-R type 2 (CD120b) - present on immune cells and binds both TNFα and TNFβ Stimulation of the TNF receptors results in receptor trimerisation and activation of downstream proteins. The effect of TNFα on any cell depends on myriad co-stimuli. - CD40 co-stimulus results in FADD pathway activation; - The caspase family of enzymes cleave cellular DNA - Bid binds to inserts pores into the mitochondrial membrane, causing leakage of cytochrome c. Cytochrome c binds APAF-1 to activate the caspase family and cause cellular DNA degradation - TRAF2-ASK1 pathway activation results in AP-1 production, which binds DNA to regulate the production of many proteins - TRAF2-RIP pathway activation results in NF- κβ production, which binds DNA primer sequences and stimulates mRNA, therefore protein production and a change in cell function APAF-1 = Activating Protease Apoptotic Factor-1, AP-1 = Activator Protein 1

Summary box

Treatments for SIRS.