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A minimally invasive liver biopsy technique was tested for its applicability to study the hepatic acute phase response (APR) in dairy cows with Escherichia coli lipopolysaccharide (LPS)-induced mastitis. The hepatic mRNA expression profiles of the inflammatory cytokines, tumor necrosis factor α (TNF-α), IL-1β, IL-6, and IL-10, and the acute phase proteins serum amyloid A isoform 3 (SAA3), haptoglobin (Hp), and α1-acid glycoprotein (AGP) were determined by real-time reverse transcription-PCR. Fourteen primiparous cows in mid lactation were challenged with 200μg of LPS (n = 8) or NaCl solution (n = 6) in 1 front quarter. Six repeated liver biopsies were collected at −22, 3, 6, 9, 12, and 48h relative to LPS challenge in 4 LPS-infused cows and 3 NaCl-infused cows. The remaining cows had 3 liver biopsies taken at −22, 9, and 48h. Production data and clinical signs were recorded and white blood cell counts and somatic cell counts (SCC) were analyzed to investigate the effect of repeated liver biopsies and verify the LPS model. Plasma concentrations of TNF-α, SAA3, Hp, and AGP were determined for comparison with the liver expression data. Repeated liver biopsies had no effects on the production data, clinical signs, or APR of dairy cows. Compared with the NaCl-infused cows the LPS-infused cows responded to the LPS treatment by increased body temperature (38.6±0.1 vs. 39.4±0.1°C), short-term leukopenia followed by leukocytosis (6.44±0.4 vs. 5.69±0.3×106 cells/mL), an increased SCC (log10 2.1±0.1 vs. log10 2.8±0.1×103 cells/mL), heart rate (76±1 vs. 93±1 beats/min), and respiratory rate (32±2 vs. 36±1 breaths/min) in the acute phase of the disease. The LPS treatment upregulated the hepatic expression of TNF-α (103±24 vs. 255±18 units), IL-1β (37±23 vs. 296±18 units), IL-6 (8±17 vs. 122±12 units), and IL-10 (130±66 vs. 541±50 units), and SAA3 (64±36 vs. 128±28 units) and Hp (9±82 vs. 762±65 units) reaching maximum levels at 3 to 6h and 9 to 12h postinfusion, respectively. Plasma concentrations of TNF-α (nondetectable vs. 1.9±0.3 ng/mL), SAA (19.8±19.4 vs. 149.7±15.5μg/mL) and Hp (71.4±143.7 vs. 1,013.8±111.5μg/mL) were elevated in the LPS-infused cows at 4 to 12h, 8 to 120h, and 24 to 120h postinfusion, respectively. The hepatic expression of AGP and the AGP plasma concentration remained unaltered in LPS-induced cows. In conclusion, a minimally invasive liver biopsy technique can be used for studying the hepatic APR in diseased cattle. Lipopolysaccharide-induced mastitis resulted in a time-dependent production of inflammatory cytokines and SAA and Hp in the liver of dairy cows.

BackgroundBlood serum and peritoneal fluid acute-phase proteins, oxidative stress indicators, and some enzymes could be used for evaluation of abomasal tissue damage because of displacement in displaced abomasum (DA) cases.ObjectivesThe aim of this study was to investigate the concentrations of acute-phase proteins, oxidative stress indicators, and activities of enzymes in blood serum and peritoneal fluid in cattle with right displaced abomasum (RDA) and left displaced abomasum (LDA) and in healthy cows.AnimalsA total of 60 Holstein Friesian cows in early lactation were used, 31 with left and 9 with right displaced abomasum without volvulus diagnosis and no other postpartum disease, and 20 healthy cows as a control.Materials and MethodsDA diagnosis in dairy cows consisted of physical examination, laboratory, and specific DA tests. Acute-phase proteins, oxidative stress indicators, and enzyme activities were measured in blood serum and peritoneal fluid.ResultsIn the RDA group, serum haptoglobin (HPG), serum amyloid A (SAA), malondialdehyde (MDA), adenosine deaminase (ADA), myeleperoxidase (MPO), aspartate aminotransferase (AST), creatine kinase (CK, creatine kinase–MB (CK-MB), and gamma-glutamyl transferase (GGT) activity increased significantly, and serum HPG, MDA, ADA, and AST concentrations increased significantly in the LDA group (P < .05). Peritoneal fluid HPG, MDA, ADA, MPO, ALP, GGT, and LDH concentrations increased significantly, whereas NO concentrations reduced significantly in the RDA group, and HPG, MDA, ADA, and TP concentrations increased significantly, whereas concentrations of NO reduced significantly in the LDA group (P < .05).Conclusions and Clinical ImportanceThere are acute-phase responses, oxidative stress, and abomasal tissue damage because of displacement in DA cases. Especially, HPG, MDA, ADA, and MPO concentrations can provide specific information to help in understanding these changes.

Haemoglobin genotype S is known to offer protection against infections but the mechanism underlying this protection is not completely understood. Associated changes in acute phase proteins (APPs) during infections between Haemoglobin AA (HbAA) and Haemoglobin AS (HbAS) individuals also remain unclear. This study aimed to evaluate changes in three APPs and full blood count (FBC) indices of HbAA and HbAS children during infection. Venous blood was collected from three hundred and twenty children (6 months to 15 years) in Begoro in Fanteakwa District of Ghana during a cross-sectional study. Full blood count (FBC) indices were measured and levels of previously investigated APPs in malaria patients; C-reactive protein (CRP), ferritin and transferrin measured using Enzyme-Linked Immunosorbent Assays. Among the HbAA and HbAS children, levels of CRP and ferritin were higher in malaria positive children as compared to those who did not have malaria. The mean CRP levels were significantly higher among HbAA children (p=0.2e-08) as compared to the HbAS children (p=0.43). Levels of transferrin reduced in both HbAA and HbAS children with malaria, but the difference was only significant among HbAA children (p=0.0038), as compared to the HbAS children. No significant differences were observed in ferritin levels between HbAA and HbAS children in both malaria negative (p=0.76) and positive (p=0.26) children. Of the full blood count indices measured, red blood cell count (p=0.044) and haemoglobin (Hb) levels (p=0.017) differed between HbAA and HbAS in those without malaria, with higher RBC counts and lower Hb levels found in HbAS children. In contrast, during malaria, lymphocyte and platelet counts were elevated, whilst granulocytes and Mean Cell Haematocrit counts were reduced among children of the HbAS genotypes. Significant changes in APPs were found in HbAA children during malaria as compared to HbAS children, possibly due to differences in malaria-induced inflammation levels. This suggests that the HbAS genotype is associated with better control of infection-induced inflammatory response than HbAA genotype.

1. Thermoregulation and pathogen resistance are two energetically demanding processes that co-occur during seasonal epidemics for many endothermic vertebrates. The ability of hosts to cope with these processes simultaneously may influence population-level disease dynamics. 2. In North American house finches (Carpodacus mexicanus), outbreaks of the bacterium Mycoplasma gallisepticum occur during fall and winter, when ambient temperatures across the host's range are often below thermoneutrality. Here, we examined how ambient temperature influences host energetics and susceptibility to this naturally occurring seasonal pathogen by experimentally infecting wild-caught house finches with M. gallisepticum at either thermoneutral or subthermoneutral temperatures in the laboratory. We quantified the metabolic costs of infection, measures of body condition, two components of the acute-phase response, disease expression and pathogen loads under both temperature regimes. 3. The metabolic costs of simultaneous infection with M. gallisepticum and thermoregulation were additive and significant (combined costs of 4·71 kJ per night; within the range of the daily energy requirements of passerine moult). Contrary to our predictions, house finches at subthermoneutral temperatures had lower disease expression and higher circulating levels of the cytokine interleukin-6 in response to experimental infection with M. gallisepticum than finches at thermoneutral. However, pathogen loads did not differ between the two temperature treatments. Finches from both treatments expressed fever in response to infection, but the magnitude of fever did not vary with ambient temperature. 4. Despite the significant energy costs of infection and thermoregulation, house finches from both temperature treatments maintained body mass and pectoral muscle condition, suggesting that birds housed at subthermoneutral consumed more food to maintain energy balance. In the field, competition for finite resources would be expected to exacerbate the effects found here and force infected birds to spend more time at feeders where M. gallisepticum is transmitted. 5. Overall, our results indicate that moderate cold stress alters house finch immunity, energetics and disease pathology, but does not alter infectiousness as measured by pathogen load. The effects of ambient temperature on host response and energy demands could directly or indirectly contribute to seasonal and geographical variation in disease dynamics in free-living house finches. More broadly, our results suggest that even subtle changes in abiotic factors such as temperature can alter host disease expression, with broad implications for disease dynamics.

Background Swine influenza (SI) is a contagious, important respiratory disease. Diagnosis of SI is based on the clinical signs, confirmed by the detection of viral RNA or specific antibodies. However, the infection is much more frequent than the disease. Objectives The aim of study was to investigate the kinetics of acute‐phase protein (APP) response during subclinical and clinical influenza in pigs. The utility of APP measurements in identification of infected animals was also evaluated. Methods Twenty‐eight piglets were used. C‐reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA) and pig major acute‐phase protein (Pig‐MAP) concentrations in serum were measured using commercial ELISAs. Results and Conclusions No relevant clinical signs were observed in intranasally infected pigs. In contrast, coughing, nasal discharge, and fever were observed in pigs infected intratracheally. All infected pigs exhibited specific antibodies in the serum at 10 dpi, and viral shedding was confirmed. The concentrations of CRP, Hp and SAA were significantly increased after infection. The level of Pig‐MAP remained constant during subclinical and clinical infection. The concentrations of CRP, Hp and SAA were higher in pigs with clinical disease. Although not specific, strategic APP measurements may reveal ongoing clinical and subclinical infection. A close relationship between the magnitude of serum APP response with the severity of disease, providing an objective tool for validation the severity of infection. The maximum concentration of SAA in serum was closely correlated with lung score and makes this APP potential indicator for disease progress or estimation of treatment strategy.

Serum amyloid A (SAA) proteins were isolated and named over 50 years ago. They are small (104 amino acids) and have a striking relationship to the acute phase response with serum levels rising as much as 1000-fold in 24 hours. SAA proteins are encoded in a family of closely-related genes and have been remarkably conserved throughout vertebrate evolution. Amino-terminal fragments of SAA can form highly organized, insoluble fibrils that accumulate in “secondary” amyloid disease. Despite their evolutionary preservation and dynamic synthesis pattern SAA proteins have lacked well-defined physiologic roles. However, considering an array of many, often unrelated, reports now permits a more coordinated perspective. Protein studies have elucidated basic SAA structure and fibril formation. Appreciating SAA’s lipophilicity helps relate it to lipid transport and metabolism as well as atherosclerosis. SAA’s function as a cytokine-like protein has become recognized in cell-cell communication as well as feedback in inflammatory, immunologic, neoplastic and protective pathways. SAA likely has a critical role in control and possibly propagation of the primordial acute phase response. Appreciating the many cellular and molecular interactions for SAA suggests possibilities for improved understanding of pathophysiology as well as treatment and disease prevention.

The development of cachexia in the setting of cancer or other chronic diseases is a significant detriment for patients. Cachexia is associated with a decreased ability to tolerate therapies, reduction in ambulation, reduced quality of life, and increased mortality. Cachexia appears intricately linked to the activation of the acute phase response and is a drain on metabolic resources. Work has begun to focus on the important inflammatory factors associated with the acute phase response and their role in the immune activation of cachexia. Furthermore, data supporting the liver, lung, skeletal muscle, and tumor as all playing a role in activation of the acute phase are emerging. Although the acute phase is increasingly being recognized as being involved in cachexia, work in understanding underlying mechanisms of cachexia associated with the acute phase response remains an active area of investigation and still lack a holistic understanding and a clear causal link. Studies to date are largely correlative in nature, nonetheless suggesting the possibility for a role for various acute phase reactants. Herein, we examine the current literature regarding the acute phase response proteins, the evidence these proteins play in the promotion and exacerbation of cachexia, and current evidence of a therapeutic potential for patients.

Cancer disease describes any pathology involving uncontrolled cell growth. As cells duplicate, they can remain localized in defined tissues, forming tumor masses and altering their microenvironmental niche, or they can disseminate throughout the body in a metastatic process affecting multiple tissues and organs. As tumors grow and metastasize, they affect normal tissue integrity and homeostasis which signals the body to trigger the acute phase inflammatory response. C-reactive protein (CRP) is a predominant protein of the acute phase response; its blood levels have long been used as a minimally invasive index of any ongoing inflammatory response, including that occurring in cancer. Its diagnostic significance in assessing disease progression or remission, however, remains undefined. By considering the recent understanding that CRP exists in multiple isoforms with distinct biological activities, a unified model is advanced that describes the relevance of CRP as a mediator of host defense responses in cancer. CRP in its monomeric, modified isoform (mCRP) modulates inflammatory responses by inserting into activated cell membranes and stimulating platelet and leukocyte responses associated with acute phase responses to tumor growth. It also binds components of the extracellular matrix in involved tissues. Conversely, CRP in its pentameric isoform (pCRP), which is the form quantified in diagnostic measurements of CRP, is notably less bioactive with weak anti-inflammatory bioactivity. Its accumulation in blood is associated with a continuous, low-level inflammatory response and is indicative of unresolved and advancing disease, as occurs in cancer. Herein, a novel interpretation of the diagnostic utility of CRP is presented accounting for the unique properties of the CRP isoforms in the context of the developing pro-metastatic tumor microenvironment.

C-reactive protein (CRP) is one of the major members of the family of acute phase proteins (APP). Interest in this CRP was the result of a seminal discovery of its pattern of response to pneumococcal infection in humans. CRP has the unique property of reacting with phosphocholine-containing substances, such as pneumococcal C-polysaccharide, in the presence of Ca 2+ . The attention regarding the origin of CRP and its multifunctionality has gripped researchers for several decades. The reason can be traced to the integrated evolution of CRP in the animal kingdom. CRP has been unequivocally listed as a key indicator of infectious and inflammatory diseases including autoimmune diseases. The first occurrence of CRP in the evolutionary ladder appeared in arthropods followed by molluscs and much later in the chordates. The biological significance of CRP has been established in the animal kingdom starting from invertebrates. Interestingly, the site of synthesis of CRP is mainly the liver in vertebrates, while in invertebrates it is located in diverse tissues. CRP is a multifunctional player in the scenario of innate immunity. CRP acts as an opsonin in the area of complement activation and phagocytosis. Interestingly, CRP upregulates and downregulates both cytokine production and chemotaxis. Considering various studies of CRP in humans and non-human animals, it has been logically proposed that CRP plays a common role in animals. CRP also interacts with Fcγ receptors and triggers the inflammatory response of macrophages. CRP in other animals such as primates, fish, echinoderms, arthropods, and molluscs has also been studied in some detail which establishes the evolutionary significance of CRP. In mammals, the increase in CRP levels is an induced response to inflammation or trauma; interestingly, in arthropods and molluscs, CRP is constitutively expressed and represents a major component of their hemolymph. Investigations into the primary structure of CRP from various species revealed the overall relatedness between vertebrate and invertebrate CRP. Invertebrates lack an acquired immune response; they are therefore dependent on the multifunctional role of CRP leading to the evolutionary success of the invertebrate phyla.

Background Acute phase response (APR) is characterized by a change in concentration of different proteins, including C-reactive protein and serum amyloid A (SAA) that can be linked to both exposure to metal oxide nanomaterials and risk of cardiovascular diseases. In this study, we intratracheally exposed mice to ZnO, CuO, Al 2 O 3 , SnO 2 and TiO 2 and carbon black (Printex 90) nanomaterials with a wide range in phagolysosomal solubility. We subsequently assessed neutrophil numbers, protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, Saa3 and Saa1 mRNA levels in lung and liver tissue, respectively, and SAA3 and SAA1/2 in plasma. Endpoints were analyzed 1 and 28 days after exposure, including histopathology of lung and liver tissues. Results All nanomaterials induced pulmonary inflammation after 1 day, and exposure to ZnO, CuO, SnO 2 , TiO 2 and Printex 90 increased Saa3 mRNA levels in lungs and Saa1 mRNA levels in liver. Additionally, CuO, SnO 2 , TiO 2 and Printex 90 increased plasma levels of SAA3 and SAA1/2. Acute phase response was predicted by deposited surface area for insoluble metal oxides, 1 and 28 days post-exposure. Conclusion Soluble and insoluble metal oxides induced dose-dependent APR with different time dependency. Neutrophil influx, Saa3 mRNA levels in lung tissue and plasma SAA3 levels correlated across all studied nanomaterials, suggesting that these endpoints can be used as biomarkers of acute phase response and cardiovascular disease risk following exposure to soluble and insoluble particles.