Acute Phase Proteins response and their clinical application in veterinary medicine

Acute-phase proteins (APP) are a group of blood proteins that the synthesis happens quickly and intensely in response to external or internal challenges, such as infection, inflammation, surgical trauma, or stress. These proteins have been used as biomarkers of inflammation, infection, and trauma in human medicine, but have been relatively under-utilized in the context of veterinary medicine due to the unknown diagnostic possibilities. The purpose of this paper is to update the knowledge about APPs in veterinary medicine, reviewing results from different studies suggesting possible clinical applicability of APPs measurement as a valuable tool for veterinary diagnostic and prognostic. In a study Löfqvist et al., (2018) investigated the changes in concentrations of the systemic inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) following tibial plateau leveling osteotomy (TPLO) in dogs and evaluate if deviations from the changes expectedly induced by the surgical procedure are useful in early detection of post-surgical infections. A characteristic pattern of changes in concentrations of CRP and SAA were observed following TPLO with a significant increase 24 h post-surgery in all dogs and baseline-concentrations re-established at day 12, these results confirm the alterations on the APP levels after surgical injury and the utility of measurement as a tool on the prognostic of dogs submitted to TPLO. insulin-like C-reactive


Introduction
Acute-phase proteins (APP) have been used as biomarkers of inflammation, infection, and trauma for decades in human medicine, but have been relatively under-utilized in the context of veterinary medicine due to the unknown diagnostic possibilities.
The APP is the group of blood proteins that the synthesis happens quickly and intensely as a systemic reaction to local or systemic disturbances caused by trauma, infection, stress, surgery, neoplasia, or inflammation the goal of which is re-establishment of homeostasis and healing. The systemic functions related to the host defense response in infection and inflammation, as the stimulation of angiogenesis and granulocyte activity (ALSAAD, 2011). C-reactive protein (CRP) is a 115 kDa protein, consisting in five subunits. Originally named for its ability to bind the C-polysaccharide of Pneumococcus pneumoniae. CRP functions are dependent on its binding to bacteria and promote the binding of complement, which facilitates bacterial uptake by phagocytes. Other biological CRP functions include the induction of cytokines by monocytes and macrophages, inhibition of chemotaxis, and modulation of neutrophil functions (MURATA et al., 2004).
Free native Serum amyloid A (SAA) is a 180-kDa protein, which is normally found in a complexed form with lipoproteins. It is thought to be the precursor of amyloid protein A, the major protein source of alpha-amyloid, so it is potentially involved in the pathogenesis of amyloidosis and other chronic inflammatory diseases. One of the biological activities is its chemotactic effect on monocytes, polymorphonuclear, and T cells (PETERSEN; NIELSEN; HEEGAARD, 2004).
Alpha 1 acid glycoprotein (AGP) is mainly synthesized and secreted by hepatocytes. Local AGP may contribute to the maintenance of homeostasis by reducing the tissue damage associated with the inflammatory process.
Systemic AGP has been reported to bind drugs and to participate in immunomodulation. For example, serum albumin, the most important drugbinding protein, AGP binds with and carries substances of endogenous or exogenous origin such as heparin, histamine, serotonin, and steroids. This capacity might help to keep total drug binding levels unaffected in acute phase responses in which serum albumin, a negative APP, decreases in concentration (MURATA et al., 2004).
Ceruloplasmin (CP) is a cooper-containing ferroxidase that oxidizes toxic ferrous iron to its non-toxic ferric form. Cp is synthesized primarily in the liver, but is also induced at extra-hepatic sites and may act as an antiinflammatory agent by reducing the number of neutrophils attaching to the Vet. Not. | Uberlândia, MG | v.26 | n.1 | p.82-111 | jan./jun. 2020 | ISSN 1983-0777 Alves, Mota, Fujimoto, Sousa, Filippo Acute Phase Proteins response and their clinical… 86 endothelium and by acting as an extracellular scavenger of peroxide (MURATA et al., 2004).
Fibrinogen is a β-globulin present in the plasma of all vertebrates. It is involved in homeostasis, providing a substrate for fibrin formation and tissue repair, and a matrix for the migration of activated cells (LEBRETON, CASINI 2016).
Albumin is the most abundant protein in the blood, constituting 35-50% of the protein in the plasma of healthy animals. It is the major band observed in serum protein electrophoretograms. Albumin is responsible for about 75% of the osmotic pressure of plasma and is a major source of amino acids that can be utilized by the animal's body (CERÓN; ECKERSALL; MARTÍNEZ-SUBIELA, 2005).
Transferrin is a plasma glycoprotein responsible for the transport of iron in the circulation; it has a single polypeptide chain of about 700 amino acids. It is a negative APP and involved in innate immunity, probably by sequestering ferric ions to prevent pathogens and parasites from using nutrients (LAW, 2002 respectively to the same proteins cited previously (Table 1). During the postoperative period, the group of queens submitted to laparoscopy presented the lowest values as compared with the control group. In this group, there a peak followed by a decrease in white blood cell count was observed within 24 h, while in the laparoscopy group the peak was observed 12 h after surgery. The number of leucocytes was higher in animals submitted to conventional ovariectomy than in animals submitted to laparoscopy. Possibly due to the action of cortisol released in animals under stress, pain and immediate post-operative situation that are observed in both operative procedures but probably more severe when the conventional technique is applied (Table 2).  These results indicate that increase or decrease of acute-phase proteins, as well as white blood cell count, may be a useful indicator to evaluate the inflammatory response induced by these surgical procedures. It is possible that the analysis of these parameters in the post-operative period may be In bitches, the APP serum level assessment has been used to early pregnancy diagnosis for appropriate medical assistance insuring normal gestation and indicating abortion of embryonic resorption or interruption of undesirable pregnancy. The APP profile on early pregnancy vary as a consequence of generalized inflammatory reaction due to embryonic endometrial invasion and use alterations as a method for early pregnancy diagnosis. The relationship between hormonal status and acute-phase proteins concentrations has been assessed. In one study weekly serum samples were collected from 20 non-pregnant (NP) and 20 pregnant (P) bitches to determine levels of fibrinogen, haptoglobin, ceruloplasmin, seromucoid, glycoprotein, α2 globulin, progesterone, and estradiol-17b. No correlation was found between the implantation sites formed (number of pups born) and the hepatic stimulus for the APP production. Authors conclude that in bitches, APP can be used as an early pregnancy test from the 3rd week of gestation using the haptoglobin assay (values above 112.42 mg/dl), from the 4th to the 6th week using the ceruloplasmin test (values above 12:76_ 5:29 U/l), from the 4th week for using the alpha-acid glycoprotein test (values above 13.67%) and from the 4th week of gestation using the α2-globulin test (values above 0.61 g/dl). Fibrinogen and seromucoid increased in the pregnant According to Rota et al., (2019), an increase in CRP concentration has been detected in the first or second trimester of pregnancy in the bitch, followed by a decrease before parturition. A second increase after parturition has been occasionally observed. Implantation of the developing embryo in the endometrium and placental development were suggested as the likely cause of acute phase response and it has also been ascribed as 'the influence of endocrine hormones during pregnancy. In the past, the analysis of CRP and other APP concentrations was proposed as an approach for early pregnancy diagnosis in the bitch. Although the exact mechanisms responsible for parturition are still to be elucidated. A precise prediction of impending parturition could be very useful to avoid long observation periods and is very important when planning a cesarean section. Serum progesterone concentration decreases before parturition and other easily measurable variables that could allow for determination of the onset of parturition would be very useful in clinical practice. C-reactive protein (CRP) is one of the major acute-phase proteins in dogs and the concentrations of this protein was measured around parturition and to verify whether this protein could be useful, together with progesterone (P) to detect the onset of parturition in bitches. It was possible to notice that the increase in CRP very near the time of parturition and the low magnitude of the increase does not allow for it to be useful in clinical practice to assess the onset of parturition in the bitch.
Dynamic change of APP-serum concentrations in pregnant bitches was also correlated to ultrasound features of concepts as well as gestational age. An evaluation of the APP is recommended as a helperexamination for diagnosis of inflammatory situation in bitches with pyometra. In order to analyse the profile of blood fibrinogen, serum C-reactive protein (CRP) and leukogram, besides checking the possible correlations among these laboratory indicators in bitches clinically healthy and with pyometra, two groups were studied, one without pyometra and other with pyometra. It was observed that the total number of leukocytes, fibrinogen and CRP were higher for the group of animals with pyometra. High positive correlation was observed between CRP and fibrinogen and the latter with parameters of leukogram. It can be concluded that leukocytes, fibrinogen and CRP analysis may be recommended as coadjutants examination in the diagnosis of the inflammatory process of bitches with pyometra (CARVALHO et al., 2008).
A study reported the evolution of serum levels of insulin-like growth factor-1 (IGF-1) and C-reactive protein (CRP) in bitches with ovariohysterectomy after diagnostic of pyometra in comparison with the control group of healthy bitches submitted to the surgery and the results showed that these markers could be useful for assessment of the postoperative period due the serum level of IGF-1 is decreased, whereas CRP is increased during severe inflammation. When inflammation caused by pyometra and surgery was performed, the level of IGF-1 was increased and CRP decreased (DABROWSKI et al., 2015).
In Hp has also been associated with bacterial infection of the uterus and delayed uterine involution (SHELDON et al., 2001). However, it has been reported that Hp concentrations remain low in acute postpartum metritis, in contrast high concentrations were only seen in cases of severe metritis (HIRVONEN et al., 1999). In dairy cows with toxic puerperal metritis, antimicrobial therapy was associated with a decrease of serum Hp concentrations. Following surgical castration of 14-month old bulls, a higher plasma Hp concentration has been observed when compared to banded and entire bulls (FISCHER et al., 2001). A higher Hp serum concentration has also been reported following ruminotomy (MORIMATSU et al., 1992). Hp serum concentration increased in experimentally-induced mastitis (HIRVONEN et al., 1999) and in field infections of different etiologies.
In horses, increased Hp serum or plasma concentration has been Alves, Mota, Fujimoto, Sousa, Filippo Acute Phase Proteins response and their clinical… 99 serum levels of Hp showed peak between three and five days post surgery, these alterations were observed by Kent and Goodall (1991). Hp increase was also observed in horses with colic (DI FILIPPO et al., 2010).
In cattle and humans the magnitude and duration of the APP response have been shown to reflect the severity of infection correlating with the amount of underlying tissue damage and inflammation (JACOBSEN et al., 2004).
Therefore, APP levels may serve as indicators of prognosis.
In horses, it has been shown that intra-articular injection of 3 µg of lipopolysaccharide (LPS) from Gram-bacteria elicits a larger SAA response than an injection of 1 µg, suggesting that APP concentrations reflect the extent of the underlying inflammation horses (JACOBSEN; HALLING-THOMSEN; NANNI, 2006).
In sheep with dystocia, high Hp levels have been shown to indicate dead lambs in uterus and consequently, increased surgical risk and a poor prognosis.
A study in horses with colic had higher APPs levels in non-survivors than in survivors (DI FILIPPO et al., 2010). In critically ill and septic foals, high fibrinogen concentration was among the most significant predictors of mortality (PEEK et al., 2006). Increased plasma concentration has been observed in carbohydrate-induced laminitis (FAGLIARI et al., 1998). Acute phase proteins could also indicate subclinical infections as well as a severity of infection. Thus, APP could be a valuable tool, for example to assess individual convalescence periods for horses recovering from respiratory infections. Alves, Mota, Fujimoto, Sousa, Filippo Acute Phase Proteins response and their clinical… 100 the external environment (e.g., the gastro-intestinal tract, mammary glands, and respiratory system), which may suggest that SAA plays a role in hostdefense mechanisms and local protection against invading microorganisms.
In In cattle, an increased SAA serum and plasma concentration has been found following experimentally-induced and naturally occurring inflammation as well as experimental and natural infections. The SAA response during viral respiratory diseases is well described (HEEGAARD et al., 2000). As for Hp, SAA responsiveness is of longer duration in virus-bacteria co-infections as compared with viral infection alone. The magnitude and lasting of the response were well correlated with the severity of the clinical signs (HEEGAARD et al., 2000;GANHEIM et al., 2003).    Scandinavia, v. 40, p. 323-333, 1999.