Acute Phase Proteins


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In a well-managed dairy herd, in addition to clinical mastitis, subclinical mastitis should be efficiently detected. The most promising parameters for monitoring subclinical mastitis are milk N -acetyl- D -glucosaminidase activity, lactose and electrical conductivity, along with some other indicators such as optical and milk flow measurements, preferably with an interquarter evaluation included in the test. The concentration of Hp in serum has been shown to dramatically increase in cows with experimental and spontaneous coliforms mastitis.

A significant correlation was found between the concentrations of Hp in the serum and milk, but the concentrations of SAA in the serum and milk were not related. No correlation was found between Hp and SAA levels in milk. SAA could distinguish between mild and moderate mastitis. Using a threshold value of 0. Hp and SAA concentrations below the detection limit were considered as good indicators of healthy udder quarters. A substantial variation in Hp and SAA concentrations in milk was observed in udder quarters with chronic subclinical mastitis.

The concentration of CRP was shown to increase in bovine milk during mastitis. It seems that the CRP does not have the best potential to be used in the detection of mastitis. SAA and Hp for the detection of bovine mastitis clinical and subclinical mastitis can be revealed by high serum concentrations of Hp and SAA.

It is also of interest that the concentration of APPs in milk from infected quarters is higher than that in noninfected quarters. By testing milk, a large number of samples are easily obtained in a way that is less stressful than obtaining a blood sample. If APPs are produced locally in the udder as a response to mastitis, they might be more rapid and sensitive markers of acute inflammation than the somatic cell count.

However, future studies on the applicability of APP in milk as markers of mastitis are needed. Following Streptococcus suis type-2 infection TTR showed a negative APR with serum concentrations reaching a significantly lower level at 2 days following infection. Negative reacting proteins are normally present in healthy animals, but will decrease in concentration due to the APR. Albumin is generally accepted as negative APP present in most species. The negative reacting protein transferrin is possibly involved in the innate immunity, perhaps by sequestering ferric ions to prevent pathogens and parasites from using nutrients.

Retinol-binding protein RBP is a small-molecular-weight protein which is the exclusive protein for the transport of vitamin A retinol in the body. The synthesis and secretion of RBP by parenchymal hepatocytes is mainly controlled by the combination with the larger, tetramer protein, transthretin.

The complex formation appears to be necessary to prevent extensive loss of the low-molecular-weight RBP through glomerular filtration. During starvation, there is no full positive response, and a general depression of hepatic protein synthesis occurs. Malnutrition and the anorectic effects of pro-inflammatory cytokines in the brain result in a negatively changed hepatic synthesis.

Moreover, there is evidence that cytokines and their cognate receptors are present in the neuroendocrine system and brain. On starvation and negative energy balance associated with most diseases, muscle proteins are catabolized for amino acid supply of the hepatic APP formation and as source of energy. Especially for those APPs which rapidly and quantitatively increase in blood, their formation may have amino acid impact.

An increased hindquarter protein catabolism exceeding the hepatic protein synthesis, and efflux of glutamine and alanine from the hindquarter was measured during a porcine-induced endotoxemia study. Some pig studies indicate positive influences of additional dietary tryptophan[ 81 ] or L -arginine. Median CRP concentration was increased in all groups with neoplastic lymphatic disorders like lymphomas, malignant lymphoma, and multiple myeloma. Hp level was specially increased in dogs with acute lymphoblastic leukemia ALL and malignant lymphoma. The median values in the dogs with ALL were significantly higher than in dogs with other neoplastic lymphatic disorders.

The APR and clinical application of monitoring APPs in dogs and cats include proper and adequate clinical interpretation. In addition, the diagnostic use of APPs and their possible application in monitoring treatment can be considered as one of the most interesting and promising practical applications of these proteins.

New and cheaper automated assays for determination of the main APPs in small animals will contribute to a wider use of these proteins as biomarkers of infection and inflammatory lesions. APP is applied as unspecific markers of clinical and subclinical infections, to discriminate between acute and chronic disease and for prognostic purposes, since the duration and magnitude of the response reflect the severity of the disease and the effect of treatment.

Canadian and American researchers showed that in immunologically naive boars moved to new facilities, an increase in Hp concentration was observed before the clinical signs of the disease were evident. The Hp concentration remained high, and the animals subsequently showed clinical signs of the disease depression, respiratory distress, and cyanosis. Higher Hp serum concentration prior to the clinical signs could be due to early, subclinical pathological conditions.

Also, lower gaining pigs were found to have higher Hp levels than gaining pigs. The serum Hp concentration increased significantly with age in conventional slaughter pigs without clinical signs but not in slaughter pigs from high health SPF- X herds, indicating that subclinical disease in conventional herds may be the cause of higher serum Hp concentration in older pigs.

Therefore, Hp seems to be a promising marker of health status by reflecting a broad spectrum of ongoing clinical as well as subclinical diseases. SAA is useful in the management of bacterial and viral infections in horses by large-scale monitoring in stables and as the prognostic tool in relation to clinical severity and the recovery of individual horses. Serum concentrations of SAA have been found to increase in foals during infection with Rhodocoocus equi , equine influenza serotype A2 H3N8 , equine herpes virus serotype 1, and Streptococcus equi.

A statistically significant association between SAA serum concentration and severity of clinical signs of respiratory disease as well as rectal temperature has been observed. However, future studies of APP in equine medicine are needed before the applicability can be assessed.

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When APPs are used to assess nonhealthy animals versus healthy ones, values of single reactants are often not sensitive enough to detect a special patient or subject in a population of livestock. However, the acute phase signal obtained for an individual animal can be enhanced when the values of positive APP rapid and slow are combined with those of rapid and slow negative AP in an index.

In starvation especially a decrease in the reactants may be expected. The index has been used as prognostic inflammatory and nutritional index PINI for human patients and as acute phase index API for cattle. Determination of APP can help to monitor herd and individual health, especially when several acute phase variables are combined in an NAPI. Turbidimetry is developed for APP in the dog, horse, and for the cat. Two-dimensional electrophoresis with mass spectrometry has been shown to be applicable to animal samples with the aim to measure APRs.

A protein chip has been developed for the measurement of Hp and SAA in human patients. Protein microarray methodology on slides has been proposed for APP in pigs. Preliminary experiments with a monoclonal antiporcine CRP and pig acute-phase sera using methodology as described offered the possibility to measure more than pig blood sample spots on a single slide. Indirectly, APP formation may be measured in biopsies by methods to assess upregulation of protein synthesis [quantitative polymerase chain reaction PCR ]. Especially the technique may be applied on samples after slaughter, or in histopathology and together with the assessment of cytokines.


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These technological developments may have crucial importance in the future if done rapidly, and at low costs, many samples can be handled, the APPs have a good future in diagnostics. This technique is for general assessment just as the erythrocyte sedimentation rate is used in internal medicine, but more sensitive and for special groups of patients such as hoses after castration or laprotomy. Determination of animal health is important.

APPs may provide an alternative means of monitoring animal health. An increased focus on the application of APP for this purpose has recently been developed. Due to a relatively short life in serum and high response in diseased animals, APP serum responses constitute a valid measure of a systemic response in diseased animals; APP serum responses constitute a valid measure of a systemic response to an initiating stimulus at the time of blood sampling.

Like rectal temperature, APP levels are not suitable for establishing a specific diagnosis but can provide information about the extent of ongoing lesions in individual animals. At the herd level, APP might be useful for determining from where the disease is spreading by providing information about the prevalence of ongoing clinical and subclinical infections indicated by the high serum concentration of selected APP and by serving as the prognostic tool, with the magnitude and duration of the APR reflecting the severity of infection.

Important points to consider before using APP as markers of animal health are the possible influence of environmental factors, handling, and other types of stress in the absence of disease. APPs have their possible use as markers of domestic animal health alone or at the herd level, for the detection and as a prognostic marker of different diseases or infections.

However, an international standardization of APP assays is needed before they can be applied for the systematic health monitoring in veterinary medicine. Source of Support: Nil. Conflict of Interest: None declared. National Center for Biotechnology Information , U. J Pharm Bioallied Sci. Author information Article notes Copyright and License information Disclaimer. Address for correspondence: Dr. Sachin Jain, E-mail: moc. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC. Abstract The varied reactions of the host to infection, inflammation, or trauma are collectively known as the acute-phase response and encompass a wide range of pathophysiological responses such as pyrexia, leukocytosis, hormone alterations, and muscle protein depletion combining to minimize tissue damage while enhancing the repair process. Keywords: Acute-phase proteins, C-reactive protein, diagnosis, haptoglobin, serum amyloid A. Mechanism of Synthesis of Acute Phase Proteins An APR is characterized, among other things, by fever and increases the numbers of peripherals leukocytes, in particulars, increasing the numbers of circulating neutrophils and their precursors.

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Acute-phase proteins: As diagnostic tool

Figure 1. Classification of Acute-phase Proteins On the basis of protein concentrations Negative acute-phase proteins The liver responds by producing a large number of APRs. On the basis of their mode of action APP classified as below: Protease inhibitors, e. Coagulation proteins, e.

Complement proteins, e. Transport proteins, e. Other proteins, e. Table 1 Biological activities of selected acute phase proteins. Pattern recognition molecules, pentraxins, and C-reactive proteins In the past, the innate immune system was considered to be a primitive static system; nowadays delve into its complexity. Functions CRP levels rise dramatically during inflammatory processes occurring in the body.

Diagnostic use CRP is used mainly as a marker of inflammation and infection. Role in cardiovascular disease Patients with elevated basal levels of CRP are at an increased risk of diabetes, hypertension, and cardiovascular disease. Diagnostic test Various analytical methods are available for CRP determination, such as enzyme linked immunosorbent assay ELISA , immunoturbidimetry, rapid immunodiffusion, and visual agglutination. Relevance of genetic vs environmental determinants of CRP Elevated plasma levels of CRP are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease.

Haptoglobin Haptoglobin Hp is a protein in the blood plasma that binds free hemoglobin released from erythrocytes with affinity and thereby inhibits its oxidative activity.

Clinical significance Haptoglobin is produced mostly by hepatocytes but also by other tissues, e. Table 2 Haptoglobin level in various species. Mannose-binding protein The most important acute phase opsonin is the Ca-dependent mannose-binding protein MBP , which can react not only with mannose but several other sugars, so enabling it to bind with an exceptionally wide variety of Gram-negative and -positive bacteria, yeasts, viruses, and parasites; its subsequent ability to trigger the classical C3 convertase through two novel associated serine proteases MASP-1 and MASP-2 qualifies it as an opsonins.

Transferrins Transferrin is a blood plasma protein for iron ion delivery. Prostate cancer penitents with bone lesions Prostate cancer has a propensity to metastasize to the bone. Hematological and neoplastic diseases of the dog Serum concentrations of APPs, Hp, Cp, SAA, and CRP were determined in healthy dog and dogs with different diseases, grouped as acute inflammation, hematological neoplasias [hemotologic tumor HT ], including epithelial, mesenchymal, and mixed and autoimmune hemolytic anemia.

Multiple myeloma Long-lasting APR occurs in patients with chronic inflammation and cancer. Mastitis In a well-managed dairy herd, in addition to clinical mastitis, subclinical mastitis should be efficiently detected. Starvation Negative reacting proteins are normally present in healthy animals, but will decrease in concentration due to the APR. Lymphatic Neoplasia Median CRP concentration was increased in all groups with neoplastic lymphatic disorders like lymphomas, malignant lymphoma, and multiple myeloma.

Some application of acute phase proteins as diagnostic tool in animals APP is applied as unspecific markers of clinical and subclinical infections, to discriminate between acute and chronic disease and for prognostic purposes, since the duration and magnitude of the response reflect the severity of the disease and the effect of treatment. Haptoglobin: A marker of herd health status in pigs Canadian and American researchers showed that in immunologically naive boars moved to new facilities, an increase in Hp concentration was observed before the clinical signs of the disease were evident.

Serum amyloid A as a prognostic marker in equine respiratory disease SAA is useful in the management of bacterial and viral infections in horses by large-scale monitoring in stables and as the prognostic tool in relation to clinical severity and the recovery of individual horses. Acute Phase Index When APPs are used to assess nonhealthy animals versus healthy ones, values of single reactants are often not sensitive enough to detect a special patient or subject in a population of livestock.

Conclusion Determination of animal health is important. References 1. Johnson RW. Inhibition of growth by pro-inflammatory cytokines; an integrated view. J Anim Sci. Baumann H, Gauldie J. Regulation of acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med. The acute phase response. Biochemistry of Inflammation. London: Kluwer Academic; Bovine and canine acute phase proteins. Vet Res Commun. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med.

Beck G, Habicht GS. Isolation and characterization of a primitive interleukin-1 like protein from an invertebrate. Asterias forbesi. Pathogenesis of porcine Actinobacillus pleuropneumoniae, Part II: Roles of proinflammatory cytokines. Can J Vet Res. Cytokines in veterinary medicine. Wallingford: CAB International; Myers M, Murtaugh MP. Cytokines in animal health and disease. New York: Marcel Dekker; Murtaugh MP. Porcine cytokines. Vet Immunol Immunopathol. The acute phase response of haptoglobin and serum amyloid A SAA in cattle undergoing experimental infection with bovine respiratory syncytial virus.

Vet Immunopathol. Sipe JD. Acute phase proteins in chronic inflammation. In: Koj A, editor. The acute phase response to injury and infection. Amsterdam: Elsevier; Acute phase proteins in cattle: Discrimination between acute and chronic inflammation. Vet Rec. Vegad JL. A textbook of veterinary General Pathology.

Lucknow: Publ. International Book distributing Co; Inflammation; pp. Beutler B, Cerami A. Cahcectin Tumor necrosis factor: An endgenous mediator of shock and inflammation. Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv Immunol. Moshage H. Cytokines and the hepatic acute phase response. J Pathol. Response of Ceruplasmin to E. Res Vet Sci.

Acute phase proteins and the systemic inflammatory response : Critical Care Medicine

Effect of hepatocyte stimulating factor and glucocorticoids on fibronectin levels. Biochem J.

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Acute phase protein values in blood of cattle; a indicator of animals with pathological processes. Achieve Filr Lebensmittel hygiene. Regulation of SAA protein expression during the acute phase response. Health status and clinical signs in relation to C-reactive protein concentrations in porcine serum. Application of acute phase protein measurements in veterinary clinical chemistry.

Vet Res. Acute phase proteins on different species: A review. How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals. J Endotoxin Res. J Clin Immunol. Pentraxins in innate immunity: lessons from PTX3. Innate Immunity: Acute phase proteins increase in response to infection. Oxford: Blackwell Publishing; Tillet WS, Francis T. Serological reactions in pneumonia with non protein somatic fractin of pneumocoocus. J Exp Med. Ridker PM. Clinical application of C- reactive protein for cardiovascular disease detection and prevention.

C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities ARIC study. Arch Intern Med.

Ann Hum Genet. Am J Hum Genet. Smith GD, Ebrahim S. Mendelian randomization: Prospects, potentials, and limitations. Int J Epidemiol. Genetically Elevated C-Reactive protein and ischemic vascular disease. The presence of two low molecular mass proteins immunologically related to 14 kilodalton serum amyloid A in the lipoprotein fraction and their decreased serum concentrations in calves with experimentally induced pneumonia. J Vet Med Sci. The acute phase reactant serum amyloid A SAA3 is a novel substrate for degradation by the metalloproteinases collagenase and stromelysin.

Biochim Biophys Acta. Acute phase proteins in serum and milk from dairy cows with clinical mastitis. Elevated extrahepatic expression and secretion of mammary-associated serum amyloid A 3 M-SAA3 into colostrum. Differential expression and secretion of bovine serum amyloid A3 SAA3 by mammary epithelial cells stimulated with prolactin or lipopolysaccharide.

A number of well-known acute phase proteins have disease prognosis importance and change in the APPs level reflects the presence and intensity of inflammation during infection or injury. Further studies are still necessary to develop our knowledge in diagnostic importance of different acute phase proteins in fish and more efforts are needed to differentiate the APPs levels in case of viral, bacterial and parasitic diseases. Abstract: The acute phase proteins are biochemically and functionally unrelated protein predominantly synthesized in the liver.

Volume 24 , Issue 1 , Journal Home. Graphical Abstract: Abstract: The acute phase proteins are biochemically and functionally unrelated protein predominantly synthesized in the liver. Keywords: Acute phase proteins, inflammation, cytokines, hepatocyte. Close Print this page.

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