Serum Acute Phase Proteins Research Articles

Characterisation of the pig acute phase protein response to road transport

The acute phase protein (APP) response was evaluated after prolonged transportation of pigs under commercial conditions. Elevated serum APP concentrations were observed in two groups of boars immediately after their arrival at a destination farm compared with within-animal control samples obtained one month later. The effect was more pronounced in the first group of pigs conveyed under average transport conditions (Transport 1, 24 h), although the second group was transported for a longer time period (Transport 2, 48 h) but in superior transport conditions. In a second trial, pigs were sampled before transport, on arrival at an abattoir (following 12 h transport), and at the slaughter-line (after 6 h lairage). Significant increases in major acute phase protein (Pig-MAP), haptoglobin, serum amyloid A, C-reactive protein, and a decrease in apolipoprotein A-I, were observed at slaughter. The results demonstrate that shipment of pigs by road can result in an APP response that is probably related to the stress of transport.

Correlation between serum prostate-specific antigen and alpha-1-antitrypsin in men without and with prostate cancer

Prostate specific antigen (PSA) is frequently used for prostate cancer (PCa) screening, but serum levels are also increased by prostate inflammation. Elevations in serum levels of alpha1-antitrypsin (ATT), a marker of inflammation, in cancer patients are well documented. However, an association between PSA and ATT has never been investigated. The authors, therefore, measured serum acute phase proteins (APPs) ATT, alpha1-acid glycoprotein, C-reactive protein, and alpha1-antichymotrypsin in 174 men without and 34 with newly diagnosed untreated PCa (38-80 years old). As expected, men with PCa had higher mean PSA levels than those without PCa (P < 0.00001). Men with PCa and those without PCa but with PSA >2 ng/mL (n = 68) had significantly higher ATT concentrations than those without these conditions (n = 106) (mean +/- SEM g/L): 1.94+/-0.083, 1.92+/-0.066, 1.25+/-0.043, respectively; p <0.005). Interestingly, African-American men without PCa (n=111) had higher ATT levels than Caucasian men (n=63) (1.565+/-0.045 g/l versus 1.395+/-0.056 g/l; p <0.005); and differences persisted in men with PSA >2 ng/ml (2.094+/-0.07 g/l versus 1.593 for all0.095 g/l; p<0.0002). There were no differences among groups in the levels of other APP. ATT showed the strongest correlation with PSA (r = 0.346 to 0.395; p <0.001) than any other APP (r < or =0.245). Our data suggest that men with PCa have higher ATT levels than those without PCa; and African-American men without PCa have higher ATT levels than Caucasian men. The possible implications of elevated ATT levels in African-American men on the risk of PCa are discussed.

Transmission of Vesicular Stomatitis New Jersey Virus to Cattle by the Biting Midge Culicoides sonorensis (Diptera: Ceratopogonidae)

Abstract Laboratory-reared Culicoides sonorensis Wirth &amp; Jones were infected with vesicular stomatitis virus serotype New Jersey (family Rhabdoviridae, genus Vesiculovirus, VSNJV) through intrathoracic inoculation. After 10-d incubation at 25°C, these insects were allowed to blood feed on four steers. Two other steers were exposed to VSNJV through intralingual inoculation with 108 tissue culture infective dose50 VSNJV. All six steers became seropositive for VSNJV. The results demonstrate the ability of C. sonorensis to transmit VSNJV to livestock. Only the animals intralingually inoculated with VSNJV showed clinical signs in the form of vesicles at the site of inoculation. Uninfected C. sonorensis allowed to feed on the exposed animals did not become infected with VSNJV. Animals infected by C. sonorensis showed a slower antibody response compared with intralingually inoculated animals. This is probably because of different amounts of virus received via insect transmission and syringe inoculation. A significant difference was found in the serum acute-phase protein α-1-acid glycoprotein in animals that received VSNJV through C. sonorensis transmission. These animals had previously been exposed to insect attack in the field compared with intralingually inoculated animals and C. sonorensis-infected animals that had been protected from insect attack. The failure to observe clinical signs of vesicular stomatitis through transmission of VSNJV by C. sonorensis may explain widespread subclinical infections during vesicular stomatitis epidemics.

Transmission of Vesicular Stomatitis New Jersey Virus to Cattle by the Biting Midge &lt;I&gt;Culicoides sonorensis&lt;/I&gt; (Diptera: Ceratopogonidae)

Laboratory-reared Culicoides sonorensis Wirth & Jones were infected with vesicular stomatitis virus serotype New Jersey (family Rhabdoviridae, genus Vesiculovirus, VSNJV) through intrathoracic inoculation. After 10-d incubation at 25 degrees C, these insects were allowed to blood feed on four steers. Two other steers were exposed to VSNJV through intralingual inoculation with 10(8) tissue culture infective dose50 VSNJV. All six steers became seropositive for VSNJV. The results demonstrate the ability of C. sonorensis to transmit VSNJV to livestock. Only the animals intralingually inoculated with VSNJV showed clinical signs in the form of vesicles at the site of inoculation. Uninfected C. sonorensis allowed to feed on the exposed animals did not become infected with VSNJV. Animals infected by C. sonorensis showed a slower antibody response compared with intralingually inoculated animals. This is probably because of different amounts of virus received via insect transmission and syringe inoculation. A significant difference was found in the serum acute-phase protein alpha-1-acid glycoprotein in animals that received VSNJV through C. sonorensis transmission. These animals had previously been exposed to insect attack in the field compared with intralingually inoculated animals and C. sonorensis-infected animals that had been protected from insect attack. The failure to observe clinical signs of vesicular stomatitis through transmission of VSNJV by C. sonorensis may explain widespread subclinical infections during vesicular stomatitis epidemics.

Glycoprotein Changes in Non-Insulin Dependent Diabetic Rats: Effect of N-Benzoyl-D-Phenylalanine and Metformin

AbstractThe effect of N-benzoyl-D-phenylalanine (NBDP) and metformin on neonatal streptozotocin (nSTZ) induced diabetes has been studied on plasma and tissue glycoproteins. In some pathological conditions, such as cancer, rheumatoid arthritis and diabetes, there is an abnormal glycosylation of acute phase serum proteins. As most serum proteins are produced in the liver, we have examined glycoprotein metabolism in diabetic condition. To induce non-insulin-dependent diabetes mellitus (NIDDM) a single dose of streptozotocin (100 mg/kg body weight) was injected into two day old rats. After 1012 weeks, rats weighing above 150g were selected for NIDDM model. In these rat, blood glucose and plasma glycoproteins were significantly increased whereas plasma insulin was significantly decreased. There was a significant decrease in the level of sialic acid and elevated levels of hexose, hexosamine and fucose in tissues. Oral administration of NBDP and metformin to diabetic rats decreased blood glucose and plasma glycoproteins. Plasma insulin and tissue sialic acid were increased whereas tissue concentrations of hexose, hexosamine and fucose were near normal. Our study suggests that NBDP and metformin possess a significant beneficial effect on glycoproteins in addition to their antidiabetic effect.

Localization of the Lipopolysaccharide-binding Protein in Phospholipid Membranes by Atomic Force Microscopy

Lipopolysaccharides (LPS; endotoxin) activate immunocompetent cells of the host via a transmembrane signaling process. In this study, we investigated the function of the LPS-binding protein (LBP) in this process. The cytoplasmic membrane of the cells was mimicked by lipid liposomes adsorbed on mica, and the lateral organization of LBP in these membranes and its interaction with LPS aggregates were characterized by atomic force microscopy. Using cantilever tips functionalized with anti-LBP antibodies, single LBP molecules were localized in the membrane at low concentrations. At higher concentrations, LBP formed clusters of several molecules and caused cross-linking of lipid bilayers. The addition of LPS to LBP-containing liposomes led to the formation of LPS domains in the membranes, which could be inhibited by anti-LBP antibodies. Thus, LBP mediates the fusion of lipid membranes and LPS aggregates.

P.8.a.001 The role of cytokine network in the pathophysiology of suicidal depression

The present study aimed to evaluate the serum proteinogram, acute phase proteins (APPs) and immunoglobulins (Igs) of dogs experimentally infected by Rangelia vitalii in the acute phases of the disease. Banked serum samples collected on days 0, 10 and 20 during a previously reported R. vitalii experimental infection were used to analyze the serum proteinogram, APPs (C-reactive protein – CRP and alpha-1-acid glycoprotein – AGP) and Igs (IgM, IgG, IgA and IgE) in the current study. Total protein and albumin level were significantly (P < 0.05) decreased at day 10 PI and 20 PI in infected sera compared to the control sera. Alpha-1 globulin (day 10 PI) and gamma globulin (day 20 PI) were increased (P < 0.01) in infected sera. Alpha-2 globulin (days 10 and 20 PI) and beta-2 globulin (day 10 PI) were decreased (P < 0.05) in infected sera compared to control sera. Beta-1 globulin fraction did not differ statistically between sera. Serum CRP and AGP concentrations were significantly increased (P < 0.05) at days 10 and 20 PI in infected sera. IgG was increased at days 10 (P < 0.05) and 20 PI (P < 0.01) in infected sera. Furthermore, it was also observed an increase (P < 0.01) in the levels of IgM, IgA, and IgE in infected sera than control sera. We conclude that R. vitalii infection causes alterations in the proteinogram, and increases in the levels of APPs and Igs. Further studies are essentials to define the causes of these pathological changes in this disease.

Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C‐reactive protein

C-reactive protein (CRP) is an acute-phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high-titer anti-DNA antibodies and immune complex-mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18-20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis. MRL/lpr mice were treated with a single 200-mug injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti-double-stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks. Early CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP-treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia. These findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long-term maintenance of CRP-mediated protection was reversed by injection of an anti-CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25-bearing T cells.

Acute phase reaction and acute phase proteins

A review of the systemic acute phase reaction with major cytokines involved, and the hepatic metabolic changes, negative and positive acute phase proteins (APPs) with function and associated pathology is given. It appears that APPs represent appropriate analytes for assessment of animal health. Whereas they represent non-specific markers as biological effect reactants, they can be used for assessing nutritional deficits and reactive processes, especially when positive and negative acute phase variables are combined in an index. When such acute phase index is applied to separate healthy animals from animals with some disease, much better results are obtained than with single analytes and statistically acceptable results for culling individual animals may be reached. Unfortunately at present no cheap, comprehensive and easy to use system is available for assessing various acute phase proteins in serum or blood samples at the same time. Protein microarray or fluid phase microchip technology may satisfy this need; and permit simultaneous analysis of numerous analytes in the same small volume sample and enable integration of information derived from systemic reactivity and nutrition with disease specific variables. Applying such technology may help to solve health problems in various countries not only in animal husbandry but also in human populations.

Preliminary Studies of Serum Acute-Phase Protein Concentrations in Hematologic and Neoplastic Diseases of the Dog

Serum concentrations of acute-phase proteins (APPs): haptoglobin (Hp), ceruloplasmin (Cp), serum amyloid A (SAA), and C-reactive protein (CRP) were determined in healthy dogs (n = 15) and dogs with different diseases grouped as acute inflammation (I, n = 12), hematologic neoplasias (HT, including leukemia and lymphoma, n = 16), nonhematologic neoplasias (NHT, including epithelial, mesenchymal, and mixed, n = 20), and autoimmune hemolytic anemia (AIHA, n = 8). SAA and CRP were analyzed using commercially available enzyme-linked immunosorbent assay (ELISA) kits, and Hp and Cp were measured using colorimetric methods, all previously validated for use in dogs. Increased concentrations of all APPs were observed in all groups of diseased dogs, but statistical significance only was observed with Hp (I, P < .001; HT, P < .05), Cp (I, P < .05; AIHA, P < .01), and CRP (I, P < .001; HT, P < .001; AIHA, CRP P <.05). High variability in individual APPs within each group of diseases was found with no significant differences between leukemia and lymphoma as well as among different types of neoplasia. The AIHA group had smaller increases in Hp, SAA, and CRP but higher concentrations of Cp. When follow-up of individual cases was possible, a decrease in APPs generally was found in cases with favorable outcome. The results of this study suggest that neoplasia and hematologic diseases such as AIHA should be considered as possible causes of mild increases in APPs in dogs. Measurement of APPs may be helpful to assess clinical evolution and monitor treatment of these processes.

C-reactive protein: Ligands, receptors and role in inflammation

C-reactive protein (CRP) is the prototypical acute phase serum protein, rising rapidly in response to inflammation. CRP binds to phosphocholine (PC) and related molecules on microorganisms and plays an important role in host defense. However, a more important role may be the binding of CRP to PC in damaged membranes. CRP increases clearance of apoptotic cells, binds to nuclear antigens and by masking autoantigens from the immune system or enhancing their clearance, CRP may prevent autoimmunity. CRP binds to both the stimulatory receptors, FcγRI and FcγRIIa, increasing phagocytosis and the release of inflammatory cytokines; and to the inhibitory receptor, FcγRIIb, blocking activating signals. We have shown that, in two animal models of systemic lupus erythematosus (SLE), the (NZB × NZW)F1 mouse and the MRL/ lpr mouse, a single injection of CRP before onset of proteinuria delayed disease development and late treatment reversed proteinuria. Thus, in these models, CRP plays an anti-inflammatory role.

Reference maps of mouse serum acute-phase proteins: Changes with LPS-induced inflammation and apolipoprotein A-I and A-II transgenes

We present reference maps of the mouse serum proteome (run under reducing and non-reducing conditions), from control animals, from mice injected with lipopolysaccharide (LPS) to induce systemic inflammation, and from mice transgenic for human apolipoproteins A-I and A-II. Seventy-seven spots/spot chains from the reducing gels were identified by HPLC MS/MS, representing 28 distinct proteins, including a species-specific protease inhibitor, contrapsin, and high levels of carboxylesterase. The concentrations of acute-phase reactants were monitored for 96 h after LPS challenge. The greatest changes (four-fold 48 h after LPS administration) were observed for haptoglobin and hemopexin. Orosomucoid/alpha(1)-acid glycoprotein and apolipoprotein A-I increased steadily, to 50-60% above baseline at 96 h from stimulation. In mice transgenic for human apolipoprotein A-I the levels of expression of orosomucoid/alpha(1)-acid glycoprotein, alpha(1)-macroglobulin, esterase, kininogen and contrapsin were altered compared to knockout mice lacking apolipoprotein A-I. In contrast, except for the presence of apolipoprotein A-II, no statistically significant difference was observed in mice transgenic for human apolipoprotein A-II.

Human High Density Lipoproteins Are Platforms for the Assembly of Multi-component Innate Immune Complexes

Human innate immunity to non-pathogenic species of African trypanosomes is provided by human high density lipoprotein (HDL) particles. Here we show that native human HDLs containing haptoglobin-related protein (Hpr), apolipoprotein L-I (apoL-I) and apolipoprotein A-I (apoA-I) are the principle antimicrobial molecules providing protection from trypanosome infection. Other HDL subclasses containing either apoA-I and apoL-I or apoA-I and Hpr have reduced trypanolytic activity, whereas HDL subclasses lacking apoL-I and Hpr are non-toxic to trypanosomes. Highly purified, lipid-free Hpr and apoL-I were both toxic to Trypanosoma brucei brucei but with specific activities at least 500-fold less than those of native HDLs, suggesting that association of these apolipoproteins within the HDL particle was necessary for optimal cytotoxicity. These studies show that HDLs can serve as platforms for the assembly of multiple synergistic proteins and that these assemblies may play a critical role in the evolution of primate-specific innate immunity to trypanosome infection.

Serum acute phase protein concentrations after hysterectomy with and without low‐molecular‐weight heparin thrombosis prophylaxis

Background. Low-molecular-weight heparin (LMWH) is recommended for venous thrombosis prophylaxis. There are several lines of evidence that heparins exhibit anti-inflammatory properties in addition to their anticoagulant activity. Therefore, we decided to estimate the concentrations of C-reactive protein (CRP) and haptoglobin, as acute-phase proteins, in the blood serum of patients who underwent total abdominal hysterectomy with and without the LMWH administration. Method. Forty-two women were studied, including 26 patients treated with enoxaparin and a group of 16 women without thrombosis prophylaxis. Haptoglobin and CRP concentrations were measured in serum samples obtained before the operation and also 8, 24, 48, 72, 96, and 192 hr after surgery. Results. Serum CRP level measured 8 hr after the operation was significantly higher in the group without thrombosis prophylaxis, however, no statistically significant differences in the concentration of CRP between studied groups in the other time periods were found. There were no statistically significant differences in serum haptoglobin levels between the groups of patients in all time periods. Conclusion. Administration of low-molecular-weight heparin may affect CRP production, however, further studies are still needed in order to clarify the exact immunosuppressive action of heparins.

Analysis of Binding Sites in Human C-reactive Protein for FcγRI, FcγRIIA, and C1q by Site-directed Mutagenesis

Human C-reactive protein (CRP) is a classical, acute phase serum protein synthesized by the liver in response to infection, inflammation, or trauma. CRP binds to microbial antigens and damaged cells, opsonizes particles for phagocytosis and regulates the inflammatory response by the induction of cytokine synthesis. These activities of CRP depend on its ability to activate complement and to bind to Fcgamma receptors (FcgammaR). The goal of this study was to elucidate amino acid residues important for the interaction of CRP with human FcgammaRI (CD64) and FcgammaRIIa (CD32). Several mutations of the CRP structure were studied based on the published crystal structure of CRP. Mutant and wild-type recombinant CRP molecules were expressed in the baculovirus system and their interactions with FcgammaR and C1q were determined. A previous study by our laboratory identified an amino acid position, Leu(176), critical for CRP binding to FcgammaRI and work by others (Agrawal, A., Shrive, A. K., Greenhough, T. J., and Volanakis, J. E. (2001) J. Immunol. 166, 3998-4004) determined several residues important for C1q binding. The amino acid residues important to CRP binding to FcgammaRIIa were previously unknown. This study newly identifies residues Thr(173) and Asn(186) as important for the binding of CRP to FcgammaRIIa and FcgammaRI. Lys(114), like Leu(176), was implicated in binding to FcgammaRI, but not FcgammaRIIa. Single mutations at amino acid positions Lys(114), Asp(169), Thr(173), Tyr(175), and Leu(176) affected C1q binding to CRP. These results further identify amino acids involved in the binding sites on CRP for FcgammaRI, FcgammaRIIa, and C1q and indicate that these sites are overlapping.

Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment

The anti-inflammatory potential of azithromycin in chronic obstructive pulmonary disease (COPD) patients was explored following a standard oral dosing regimen. Patients with moderate and severe COPD were treated with azithromycin (500 mg, n = 16) or placebo ( n = 8) once daily for 3 days in a randomized, double blind design, to compare effects on inflammation markers with those seen in a previous study in healthy volunteers. A battery of tests was made on serum, blood neutrophils and sputum on days 1 (baseline), 3, 4, 11, 18 and 32. In comparison to placebo, azithromycin resulted in an early transient increase in serum nitrites plus nitrates (day 3), associated with a tendency towards an increase in the blood neutrophil oxidative burst to phorbol myristic acetate. Subsequently, prolonged decreases in blood leukocyte and platelet counts, serum acute phase protein (including C reactive protein) and soluble E-selectin and blood neutrophil lactoferrin concentrations and a transient decrease in serum interleukin-8 were observed. Blood neutrophil glutathione peroxidase activity showed a prolonged increase after azithromycin treatment. The biphasic facilitatory-then-inhibitory response to azithromycin seen in healthy volunteers is not so clearly detectable in COPD patients, only potential anti-inflammatory effects. Treatment for longer periods may give therapeutic anti-inflammatory benefit in these patients.

Inflammation-dependent changes in α2,3-, α2,6-, and α2,8-sialic acid glycotopes on serum glycoproteins in mice

The expression of acute-phase serum proteins increases in response to inflammatory stimuli. Most of these proteins are glycoproteins that often contain sialic acids (Sia). It is unknown, however, how the expression of Sia in these glycoproteins changes during inflammation. This study demonstrates changes in the alpha2,3-, alpha2,6-, and alpha2,8-Sia glycotopes on serum glycoproteins in response to turpentine oil-induced inflammation, based on lectin- and immunoblot analyses by using sialyl linkage-specific lectins, Maackia amurensis for the alpha2,3-Sia glycotope and Sambucus sieboldiana for the alpha2,6-Sia glycotopes, and monoclonal antibody 2-4B (mAb.2-4B) recognizing the di- and oligomers of the alpha2,8-Neu5Gc residue. There was an increase in a limited number of sialoglycoproteins containing the alpha2,3-, alpha2,6-, or alpha2,8-Sia glycotopes. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression profiles of mRNAs for the known sialyltransferases in mouse liver during inflammation indicated the up-regulated expression of beta-galactoside alpha2,3-sialyltransferases (ST3Gal I and ST3Gal III) and beta-N-acetylgalactosaminide alpha2,6-sialyltransferase (ST6GalNAc VI) as well as beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) mRNAs. Notably, ST3Gal I and III and ST6GalNAc VI are involved in the synthesis of the alpha2,3- and alpha2,6-Sia glycotopes on O-glycan chains and possibly on gangliosides, whereas ST6Gal I is specific for N-glycan chains. These results provide evidence for the inflammation-induced expression of sialyl glycotopes in serum glycoproteins. We demonstrated that inflammation significantly increased the expression of an unknown 32-kDa glycoprotein containing the alpha2,8-Sia glycotope. The mechanism for the increase in glycoprotein in inflamed mouse serum remains to be examined, as mRNA expression for all of the alpha2,8-sialyltransferases (ST8Sia I-VI) was unchanged during inflammation.

Comparison of inflammatory and acute-phase responses in the brain and peripheral organs of the ME7 model of prion disease.

Chronic neurodegenerative diseases such as prion disease and Alzheimer's disease (AD) are reported to be associated with microglial activation and increased brain and serum cytokines and acute-phase proteins (APPs). Unlike AD, prion disease is also associated with a peripheral component in that the presumed causative agent, PrPSc, also accumulates in the spleen and other lymphoreticular organs. It is unclear whether the reported systemic acute-phase response represents a systemic inflammatory response to prion disease or merely reflects central nervous system (CNS) inflammation. For this study, we investigated whether intracerebrally initiated prion disease (ME7 model) provokes splenic, hepatic, or brain inflammatory and acute-phase responses. We detected no significant elevation of proinflammatory cytokines or activation of macrophages in the spleens of these animals, despite clear PrPSc deposition. Similarly, at 19 weeks we detected no significant elevation of transcripts for the APPs serum amyloid A, complement C3, pentraxin 3, and alpha2-antiplasmin in the liver, despite CNS neurodegeneration and splenic PrPSc deposition at this time. However, despite the low CNS expression levels of proinflammatory cytokines, there was robust expression of these APPs in degenerating brains. These findings suggest that PrPSc is not a stimulus for splenic macrophages and that neither peripheral PrPSc deposition nor CNS neurodegeneration is sufficient to produce a systemic acute-phase response. We also propose that serum cytokine and APP measurements are not useful during preclinical disease. Possible consequences of the clear chronic elevation of APPs in the CNS are discussed.

The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-κB transcriptional activity in models of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial proliferation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-κB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 transgenic rat and the Lewis rat adjuvant-induced model, after daily oral administration. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, α1-acid glycoprotein (α1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstrate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-α-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-κB transcriptional activity.

Serum acute phase protein concentrations after hysterectomy with and without low-molecular-weight heparin thrombosis prophylaxis

Serum acute phase protein concentrations after hysterectomy with and without low-molecular-weight heparin thrombosis prophylaxis