Umar Farooq | Chinese Academy of Sciences (original) (raw)

Acute Phase Proteins as Early Non-Specific Biomarkers of Human and Veterinary Diseases, 2011

Over the years three different systems of classification of APP have been developed. The first sy... more Over the years three different systems of classification of APP have been developed. The first system is based on the degree of blood elevation of the APP, referred to as positive or negative APP; the second system is based on the time when APP are released during an APR; and the third system is based on the subset of cytokines responsible for stimulating gene expression of APP (Mackiewicz, 1997; Moshage, 1997). In the first system, positive APP are classified into one of three groups based upon the degree of rise in the blood concentration: type I APP, whose concentration increases by 50% (e.g. ceruloplasmin (Cp), complement factor C3, and factor C4); type II APP, whose concentration increases 2-to 5fold (e.g. fibrinogen and haptoglobin-Hp); and type III APP, whose quantity rises more than 5-fold the normal value [e.g. C-reactive protein (CRP) and serum amyloid A (SAA)] www.intechopen.com Application of Acute Phase Proteins for Monitoring Inflammatory States in Cattle 301 (Mackiewicz, 1997; Moshage, 1997). A few APP decrease during an APR and they are known as negative APP. The most studied negative APP include retinol binding protein (RBP), albumin, trasferrin, and transthyretin. Based on the time when they are released APP are classified as either first-or second-phase proteins (Kushner & Mackiewicz, 1987; Mackiewicz, 1997). Examples of the first-phase APP are SAA and CRP, whose levels rise as early as 4 h after the initiation of inflammation, peak within 1-3 d, and quickly return to baseline concentrations (Mackiewicz, 1997). Examples of the second-phase APP are Hp and fibrinogen, which increase 1-3 d after the initiation of APR, peak within 7-10 d, and decrease to baseline levels within 2 or more wk (Mackiewicz, 1997; Moshage, 1997). The third system classifies APP based on which cytokine subsets induce their gene expression (Baumann & Gauldie, 1994; Mackiewicz, 1997). Type I APP are induced by IL-1-like cytokines, including IL-1, IL-1, TNF-, and TNF-, and synergistically by IL-6-like cytokines, while type II APP are stimulated by IL-6-like cytokines alone, including IL-6 and IL-11 (Baumann & Gauldie, 1994; Mackiewicz, 1997; Moshage, 1997). C-reactive protein, SAA, and C3 are examples of type I proteins, while type II proteins include Hp and fibrinogen. At least forty different plasma proteins have been defined as APP. They include clotting proteins, complement factors, anti-proteases, and transport proteins (Samols, 2002). However, the number of APP commonly used in cattle research is smaller than in human research. In this chapter we will discuss only about 9 of the most studied APP in cattle. Recent evidence also indicates that several APP are secreted extrahepatically playing important roles in immune defenses against different pathogens populating mucosal layers in the body. In the following sections we will discuss the most recent reports regarding structures, functions, tissue expression as well as various factors that affect expression and production of SAA, Hp, LBP, soluble(s)CD14, CRP, Cp, lactoferrin (Lt), calcitonin generelated peptide (CGRP), and ferritin in cattle (i.e., dairy and beef cattle). 2. Serum amyloid A 2.1 Structure Serum amyloid A is an APP that belongs to a family of apolipoproteins that are coded by different genes with a high degree of homology between species (Uhlar, 1994; Malle, 1993). The family of SAA proteins in mammals has a MW of 12 kDa with 104 amino acids. They are very well conserved throughout evolution and have a wide range of functions. 2.2 Functions It is known that SAA is over expressed several orders of magnitude during infections and inflammation. Four different isoforms of SAA have been described in humans and mice (Uhlar & Whitehead, 1999) and seven different isoforms were reported in the blood of dairy cows (Takahashi, 2009). Among the known isoforms, SAA1 and SAA2 are the only ones reported to be overproduced during the APR and are known as acute phase (A)-SAA. They are mainly expressed in the liver hepatocytes. The third isoform, SAA3, is expressed extrahepatically by adipose tissue, mammary gland, intestinal epithelial cells, and macrophages and is present in the plasma at a very low level (Meek, 1992; Chiba, 2009; Eckhardt, 2010). The fourth isoform, SAA4, is constituitively expressed (de Beer, 1995) and does not respond to external stimuli. A recent investigation in cows with amyloidosis and chronic inflammation showed seven different isoforms of SAA in the serum (Takahashi, www.intechopen.com Acute Phase Proteins as Early Non-Specific Biomarkers of Human and Veterinary Diseases 302 2009). Larson (2005) reported production of SAA3 by ductal cells in the mammary gland of healthy lactating dairy cows. Moreover, Mukesh (2010) showed presence of SAA3 in the adipose tissue of dairy cows. However, the precise functions of these seven different isoforms of SAA in dairy cows are not known yet. Serum amyloid A is transported in blood in association with lipoprotein particles, particularly high-density lipoproteins (HDL) (Eriksen, 1980; Coetzee, 1986). During an APR, SAA replaces almost 85% of the apolipoprotein-A1 (apo-A1) and becomes the main apolipoprotein on HDL (Uhlar & Whitehead, 1999; Coetzee, 1986). The reason for replacement of apo-A1 during APR is related to the fact that SAA half-life is 75-80 min compared with that of apo-A1 of 11 h (Hoffman & Benditt, 1983). It is believed that endotoxin-lipoprotein complexes are quickly removed from circulation by liver hepatocytes (Harris, 2002; Ametaj, 2010). The shorter half-life of SAA might help in expedited clearance of endotoxin-lipoprotein complexes from circulation (Harris et al., 1998). The main known functions of SAA are to: 1) bind to lipoproteins and help in their expedited clearance from liver hepatocytes (Harris, 2002), 2) extract cholesterol from cells (van der Westhuyzen, 2007); 3) bind and activate neutrophils and macrophages (Furlaneto & Campa, 2000), 4) kill coliform bacteria (Shah, 2006). Other reported functions of SAA include suppression of lymphocyte response to antigens (Benson, 1979), inhibition of platelet aggregation (Zimlichman, 1990), and regulation of expression of tissue collagenase (Brinckerhoff, 1989). In addition, SAA has been shown to stimulate adhesion of mast cells to the extracellular matrix (Hershkoviz, 1997), migration and adhesion of T cells (Preciado-Patt, 1996), and migration, adhesion, and tissue infiltration of monocytes and neutrophils (Badolato et al., 1994). Serum amyloid A also induces mobilization of calcium (Ca) and chemotaxis in monocytes (Badolato, 1995) and enhances synthesis of eicosanoid in human monocytes (Malle, 1997). Although early research indicated that SAA in dairy cows is increased more during acute rather than chronic inflammatory conditions (Horadagoda, 1999), recent research shows that SAA is also increased during chronic conditions (Chan, 2010). This protein is also raised following experimental infection of cattle with Mannheimia haemolytica and during bovine respiratory syncytial virus infections (Horadagoda, 1994; Heegaard, 2000). 2.3 Factors that affect its expression 2.3.1 Mammary gland infections Molenaar (2009) demonstrated presence of a constituitive isoform of SAA3 in the mammary gland tissue of dairy cows. These authors reported that the expression profile of SAA3 was different in relation with stage of lactation and disease. Thus, SAA3 was high in the mammary tissue of pregnant cows, low during lactation, elevated during involution of the gland, and strongly increased during mastitis. An interesting observation of the same authors was that SAA3 was not expressed in lactational tissues of the gland (i.e., alveoli) but only in the epithelial cells lining ductal tissue of the teat. The role of SAA3 in ductal cells might be to protect the teat potential colonization of that area by bacteria during milking or suckling. Several other authors have reported elevated mammary gland SAA3 in the milk of cows and ewes with mastitis (Eckersall, 2001; Winter et al., 2003; Nielsen et al., 2004; Jacobsen et al., 2005). Moreover, experimental models of mastitis have demonstrated that SAA3 in the mammary gland is synthesized by the infected udder and is not coming from the blood (Grönlund, 2003; Eckersall, 2006). Gram-negative bacterial lipopolysaccharide (LPS) and the Gram-positive bacterial lipoteichoic acid (LTA) were shown to upregulate SAA3 in bovine mammary epithelial cells by 18.5-fold and 12.5-fold, respectively (Larson,