Molecular biology, measurement and clinical utility of the acute phase proteins

The acute phase reaction is a natural response to tissue injury and includes a range of metabolic activities which include alterations in the rate of synthesis of several proteins produced by the liver. It is recognised that the cytokines play a key role in mediating this response. Research is directed toward an understanding of this response from the stimulus through mediation to the role of the proteins produced. Measurement of the proteins in serum is of considerable value in the diagnosis, management and prognosis of many diseases that exhibit an acute phase response. Inflammation, resulting from any form of tissue injury causes an increase in concentration of a number of liver-derived plasma proteins -the acute phase proteins (APP). This response is mediated by cytokines released from cells at the site of inflammation and is accompanied by several other systemic responses such as leucocytosis, fever and muscle proteolysis. The response is markedly conserved throughout evolution and may serve to replenish inflammatory mediators and inhibitors consumed during inflammation. The differential induction of these proteins by different cytokines does, however lead to speculation over whether the nature and chronicity of inflammation may be influenced by the pattern of acute phase proteins produced and whether the defects in the system may predispose to pathological consequences (ref.1). MOLECULAR BASIS OF THE ACUTE PHASE REACTION The bulk of acute phase protein synthesis occurs in the liver parenchymal cells with increasing numbers of hepatocytes being recruited during the first few hours of the inflammatory response (ref. 2) . However synthesis of some acute phase proteins has been demonstrated in extra hepatic sites, in particular in cells of the monocytemacrophage lineage (refs. 3, 4).An enormous amount of experimental work has been undertaken using whole animals and hepatocyte cultures to characterise the mediators of the acute phase protein response. It is now clear that the full spectrum of the response can probably be attributed to interleukin 6 (IL6) acting in conjunction with interleukin-1 (IL1) and glucocorticoids. In addition, tumour necrosis factor can regulate a subset of acute phase proteins(refs. 5,6). In the rat, glucocorticoids and catecholamines may induce a2 macroglobulin synthesis without requirement of the cytokines (ref. 7). The cytokines responsible for the acute phase response are derived predominantly from activated macrophages at the site of injury though many other cell types may be capable of synthesizing them. When classified according to function it is clear that the acute phase proteins may all have roles to play in inflammation or the healing process which follows, ( Table 1 ). The rate of increase in their plasma concentration and the incremental change achieved following inflammatory stimulus in vivo, varies considerably and reflects their induction by different cytokines, their molecular size, volume of distribution and rate of metabolism both in the circulation and at the site of inflammation. Kushner (ref. 9) has defined acute phase proteins as those whose concentration increases by 25% or more following inflammation and has classified human acute phase proteins into three groups on the basis of the magnitude of their increase (Table 2) (ref. 10). During inflammation some proteins fall in concentration due to either a redistribution into the extravascular space (ref. 11) or cytokine mediated decreases in gene transcription (ref. 12). This group mainly contains transport proteins and includes, albumin, prealbumin, transferrin, retinol binding protein, alpha and beta lipoprotein and alpha 2 HS glycoprotein. KINETICS OF THE ACUTE PHASE RESPONSE In man CRP and serum amyloid A (SAA) show the greatest response to injury although the rate of increase in plasma concentration and the incremental change achieved following the inflammatory stimulus varies considerably between the acute phase proteins. These variations possibly reflect the differential sensitivity to induction of synthesis although in a particular species the pattern of response to acute inflammation is constant. In chronic inflammation different patterns of response may be seen following different stimuli, in different inflammatory diseases, and following the same stimulus in different species or individuals of the same species. This complex situation may reflect alterations in the rate of synthesis of individual proteins in response to changes in regulating mediator patterns. Glibetic and Baumann (ref. 13) showed that during the progression from acute (less than 24 hours after injury) to