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Acute phase reaction

The term acute phase response summarizes a number of very complex endocrine and metabolic or neurological changes observed in an organism, either locally or systemically, a short time after injuries or the onset of infections, immunological reactions, and inflammatory processes (see also: Neuroimmune network). Each form of injury or tissue disorder that precipitates an inflammatory response inevitably also causes an acute phase reaction (see also: inflammation, wound healing).

An acute phase reaction is characterized, among other things, by fever, and an increase in the numbers of peripheral leukocytes, in particular an increase in the numbers of circulating neutrophils and their precursors. At the same time one observes cellular and biochemical alterations, in particular the coordinated synthesis of so-called acute phase proteins (APP) or acute phase reactants (APR) by hepatocytes in the liver (Ruminy et al, 2001; Gabay and Kushner, 1999). Induction of the expression of these proteins is a feature also of neuroinflammation (McGeer and McGeer, 2001) and has been reported also to occur locally in the eye in diabetic retinopathy (Gerhardinger et al, 2005)

The acute phase reaction is initiated and mediated by a number of cytokines with inflammatory activities secreted by a variety of cell types (polymorphonuclear leukocytes, fibroblasts, endothelial cells, monocytes, lymphocytes etc.). The cascades of inflammatory cytokines in different tissues represent amplification and regulatory pathways controlling the development of acute phase responses in vivo. Therefore, this reaction is a direct consequence of the biological activities of an organism's own mediator substances and not the result of intrinsic properties of the infectious and/or inflammatory agents per se.

Regulation of acute phase reactions and Synthesis of acute phase proteins.

Inflammatory cytokines such as IL6, IL1, TNF, and others such as TGF, IFN, and LIF are produced by inflammatory cells. They induce local and systemic reactions. Among other things these mediators are involved in cell activation of leukocytes, fibroblasts, endothelial cells, and smooth muscle cells, inducing the synthesis of further cytokines. These mediators also have direct actions in hepatocytes of the liver. Activities are enhanced indirectly by activation of the pituitary/adrenal gland axis, which involves synthesis of ACTH and subsequent production of cortisol. Cortisol can enhance expression of IL6 receptors in liver cells and thus promotes IL6 mediated synthesis of acute phase proteins.

Negative regulatory loops can involve inhibition of synthesis of IL6, IL1, and TNF by cortisol and inhibition of the synthesis of IL1 and TNF in monocytes by IL6. Of all mediators participating in the induction and regulation of acute phase protein synthesis IL6 appears to induce the broadest spectrum of acute phase proteins whereas IL1 and TNF only induce the synthesis of subsets of these proteins.

The main mediator of the acute phase reaction is IL6, which, in turn, is regulated by IL1. In cultures of hepatocytes IL6 induces a spectrum of biochemical alterations, which more or less resemble the patterns observed also in the serum during an acute phase reaction in vivo. Like IL6, LIF and IL11 also induce an almost complete spectrum of physiological changes. A much more restricted pattern of alterations is found with IL1 and TNF with each of them showing almost identical activities. Some acute phase proteins are induced also by CNTF (ciliary neurotrophic factor). Another factor stimulating hepatocytes and inducing hepatic synthesis of acute phase proteins is CT-1.

Type, duration and degree of cellular activities and changes in these activities are influenced by the doses and the combinations of the different cytokines and also by the order in which individual factors act upon a particular target cell.

A variety of low molecular weight substances normally acting on the cells also play a major role in the sequence of events. Glucocorticoids, for example, are of particular importance for the progression of the acute phase reaction because their synthesis can be influenced by a number of cytokines, and they also, in turn, influence the synthesis of cytokines. In hypophysectomized individuals one observes a pronounced reduction of the synthesis of acute phase proteins (see also: inflammation, Systemic inflammatory response syndrome).


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