The Acute Phase

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The 'acute-phase' (AP) response is a group of physiological changes that occur after the onset of an inflammatory process or other infections and include an increase in the blood level of various proteins (known as acute-phase proteins). The function of this is to protect the host by isolating pathogens, which minimizes tissue damage and promotes healing for the restoration of homeostasis [1]. At the site of inflammation, certain white blood cells e.g. macrophages and neutophils produce certain cytokines/interleukins (ILs) IL-1 (IL-1α and IL-1β), IL-6, tumour necrosis factor α (TNF-α), interferon γ and growth promoters, which induce a number of responses in the site of infection including: inducing further cytokine production, which in turn induce a systemic response in the host (increased cell production, fever, metabolic changes in certain organs etc.); attracting inflammatory cells from the bloodstream to the site of infection by inducing the expression of selectin on nearby endothelial cells [2]; and promoting optimum antibacterial activity in recruited cells.

During the AP response, there are several changes to the concentrations of certain plasma proteins, known as acute-phase proteins. An acute-phase protein is a protein whose concentration increases (positive acute-phase protein) or decreases (negative acute-phase protein) by at least 25 percent during inflammation [3]. Components of the acute phase response usually increase together, but not all of them increase uniformly in patients that have the same condition. This suggests that AP proteins are individually regulated through differences in the patterns of production in cytokines [4]. These proteins are made in the liver and carry a wide range of functions during inflammattion. Pentraxins are a major group of AP proteins and are known as C-reactive protein (CRP) in man and serum amyloid P (SAP) component in mice. CRP's concentration is seen to increase by as much as 1000-fold during inflammation and functions in activating complement through the classical pathway and modulating the function of phagocytes, which suggests it plays a role in opsonization of infected cells [5]. The concentration of certain complement components (C1s, C2, C3,C4, C5, C9 C4b-binding protein, C1 inhibitor, mannose-binding protein and factor B) also increase during the AP response. These components, as does mannose-binding lectin, have pro-inflammatory roles during the AP response.

Minor or intermediate AP proteins, whose concentration increases in the range of three times their initial concentration include: (i) the transport proteins haptoglobin and haemopexin, which have been suggested to have an anti-inflammatory action by protecting against reactive oxygen species [4]. Haptoglobin has also said to be involved in wound healing by inducing angiogenisis [6]; (ii) the coagulation factor fibrinogen which is also involved in tissue repair by causing endothelial-cell adhesion; (iii) the proteinase inhibitor a1-antichymotrypsin which counteracts proteolytic enzymes and inhibits the generation of superoxide anions [7]. Negative AP proteins (whose concentration decreases during the AP response) include albumin, transferrin and apolipoprotein A 1 (Apo-A1).

Serum Amyloid A

The serum amyloid A (SAA) family, synthesized primarily in the liver is divided into two main groups: acute-phase SAAs (A-SAAs) and constitutive SAAs (C-SAAs). The SAA protein was named so because it was found to be the plasma precursor of amyloid A (AA), which is a main component of secondary amyloid plaques found in major organs as an occasional consequence of chronic inflammation [8]. A-SAA is a multifunctional apolipoprotein that is involved in metabolism and cholesterol transport. Its plasma concentration has been shown to increase by up to 1000-fold to an excess of 1 mg.mL-1 within the first 48 hours of the AP response [9]. This suggests it plays an important and beneficial role in the host.

SAA genes and proteins have been described for several mammalian species with those genes of human and mice being studied most extensively. There is a high degree of conservation of these genes maintained through evolution for mammals [10] which further suggests the biological importance of the SAA proteins. All the SAA genes described so far share the same four-exon and three-intron organization. This setup is common for many apolipoproteins [11]. There are four members in the human SAA gene family and five members in the mouse family. A new revised nomenclature has been adapted for naming SAA genes in order to define homologs between different species [12]. Human SAA1 and SAA2 genes and mouse Saa1 and Saa2 genes all encode A-SAAs. There is strong evidence from their transcriptional orientations and map positions that human SAA1 and mouse Saa1 are evolutionary homologs. This also applies to human SAA2 and mouse Saa2 [9]. In the mouse Saa3 is an expressed A-SAA gene, although unlike Saa1 and Saa2, it is not primarily made in the liver and appears to be a secreted product of macrophages [13]. Extraheptic production of SAA3 appears in other mammals as well e.g. rabbit, rat and hamster [10]. The rabbit SAA3 gene functions as an autocrine inducer of collagenase synthesis in synovial fibroblasts [14]. In contrast, the human SAA3 gene appears to be a pseudogene with no mRNA or protein identified so far. It was discovered that this was due to a single base insertion in exon 3 which produces a down stream stop codon [9]. Similarly, the mouse gene Saa-ps1 (originally named Saa4 [12]) is also a pseudogene. There is new evidence that suggests that the human SAA4 gene [15] and the mouse Saa5 [16] (later renamed to Saa4 [17]) gene encode for constitutive serum amyloid A (C-SAA) proteins (i.e. they are continually transcribed, even in the absence of inflammation). Although the products of these genes have been described, the function(s) of the C-SAAs are still largely unknown.

The dramatic increase in concentration of A-SAA during inflammation, as well as its high conservation over evolution suggests a critical protective role to the host during inflammation. There is, however, evidence that sustained high expression of A-SAA can lead to various clinical conditions. A-SAA is the serum precursor of amyloid A protein which is the principal component of the insoluble amyloid deposits found in organs suffering from amyloidosis [18]. This leads on to other physiological conditions and as a result increased A-SAA production has been found in Crohn's disease [19], rheumatoid arthritis [20]

During inflammation, A-SAA associates with high-density lipoprotein fraction 3 (HDL3) which replaces Apo-A1 as the main apolipoprotein on this type of HDL [10*]. This enables HDL3 to alter the cholesterol efflux from monocytes which aids the uptake and removal of cholesterol at the site of inflammation [18]. It has also been shown that when A-SAA is bound to HDL3 that it enchances the activity of secretory phospholipase which cleaves triacylglycerols into fatty acids and glycerol [12*].