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human patients with AKI have significantly higher plasma concentrations of IL-1β, IL-6, IL-8, TNF-α, C-reactive protein, and IL-10, compared with concentrations in healthy people and patients with CKD. Additionally, concentrations of IL-6, IL-8, and the

Full access
in American Journal of Veterinary Research

systemic concentrations of cytokines, which can lead to deleterious effects on immune and organ function and patient outcomes. 3 Tumor necrosis factor-α (TNF-α) and IL-1β are 2 cytokines that are increased early in equine sepsis and are known to contribute

Open access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether plasma concentrations of tumor necrosis factor-α (TNF-α) are increased in cats with congestive heart failure (CHF) secondary to cardiomyopathy.

Animals—26 adult cats with CHF and cardiomyopathy and 9 healthy control cats.

Procedure—Plasma concentrations of TNF-α were measured in cats with CHF and cardiomyopathy. Tumor necrosis factor-α was measured by quantifying cytotoxic effects of TNF-α on L929 murine fibrosarcoma cells.

Results—Concentrations of TNF-α were increased (0.13 to 3.6 U/ml) in 10 of 26 cats with CHF but were undetectable in the other 16 cats with CHF and all control cats. In 20 of 26 cats with CHF, right-sided heart failure (RHF) was evident; TNF-α concentrations were increased in 9 of these 20 cats. The remaining 6 cats had left-sided heart failure (LHF); TNF-α concentrations were increased in only 1 of these cats. Age of cats with LHF (mean ± SD, 12.1 ± 6.2 years) was not significantly different from age of the cohort with RHF (10.5 ± 5.2 years). Body weight of cats with increased TNFα concentrations (5.4 ± 1.8 kg) was not significantly different from body weight of cats with CHF that did not have measurable concentrations of TNF-α (4.7 ± 1.6 kg).

Conclusionss and Clinical Relevance—Concentrations of TNF-α were increased in many cats with CHF. Cats with RHF were most likely to have increased TNF-α concentrations. Increased plasma concentrations of TNF-α in cats with CHF may offer insights into the pathophysiologic mechanisms of heart failure and provide targets for therapeutic interventions. (Am J Vet Res 2002;63:640–642)

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in American Journal of Veterinary Research

SUMMARY

Objective

To determine the influence of brucellosis vaccination on tumor necrosis factor-α (TNF-α) con-centrations in pregnant cattle and the possible role of the bovine placenta in TNF-α production.

Animals

Polled Hereford heifers obtained from a nonvaccinated, brucellosis-free herd and bred at 16 to 27 months at age. All cattle were seronegative for Brucella abortus by results of the standard tube agglutination test.

Procedure

At 6 months' gestation, cattle were vaccinated IV with B abortus strain RB51 (n = 10), SC with B abortus strain RB51 (n = 5), or SC with B abortus strain 19 (n = 5); controls received pyrogen-free saline solution SC (n = 2). Blood samples were collected periodically for TNF-α assays. At necropsy, 8 to 12 weeks after vaccination, placental fluids and fetal blood were collected for TNF-α analysis and placental tissues were collected for immunohistochemical detection of TNF-α.

Results

Radioimmunoassays indicated no increase in TNF-α concentration in blood from IV or SC vaccinated cattle, compared with controls. Similarly, TNF-α concentrations in amniotic and allantoic fluids from SC vaccinated cattle were not different from values for controls. Although only IV vaccinated cattle developed placentitis, immunohistochemical analysis for TNF-α revealed increased immunoreactivity within placental trophoblastic epithelial cells of SC and IV vaccinated cattle.

Conclusions

SC vaccination for prevention of brucellosis, using recommended adult dosages, does not result in increase of TNF-α concentration in plasma, serum, or placental fluids; however, vaccination of pregnant cattle stimulates trophoblastic epithelial cells to express TNF-α, although the physiologic and quantitative importance of this expression remains unknown. (Am J Vet Res 1998;59:153–156)

Free access
in American Journal of Veterinary Research

Abstract

Objectives—To evaluate effects of proinflammatory mediators on phagocytosis and killing of Staphylococcus aureus, the oxidative burst (OB), and expression of receptors for opsonins by bovine neutrophils.

Sample Population—Neutrophils from 10 cattle.

Procedure—Neutrophils were primed with recombinant bovine tumor necrosis factor-α (TNF-α) or the des-arginine derivative of bovine C5a (C5adesArg) and mixed with S aureus. Phagocytosis and OB were measured by use of flow cytometry. Rate of phagocytosis and intracellular killing were evaluated. Expression of receptors for immunoglobulins and the C3bi fragment of complement were estimated by use of flow cytometry.

Results—Priming of neutrophils by TNF-α improved phagocytosis of S aureus with a concentrationdependent effect. Phagocytosis of preopsonized washed bacteria was increased by activation of neutrophils with C5adesArg. Phagocytosis was optimal when neutrophils primed with TNF-α were activated with C5adesArg. The OB of phagocytizing neutrophils was highest when TNF-α and C5adesArg were used in combination. Bactericidal activity of neutrophils was stimulated by priming with TNF-α or C5adesArg. Binding of bovine IgM or IgG2 to bovine neutrophils was not stimulated by TNF-α, C5adesArg, or both, and aggregated IgG1 did not bind to neutrophils regardless of their activation state. Both TNF-α and C5adesArg increased expression of β2 integrins (CD18), with the highest expression when they were used in combination.

Conclusions and Clinical Relevance—The mediators TNF-α and C5adesArg stimulated phagocytic killing by neutrophils and potentiated each other when used at suboptimal concentrations. Bovine neutrophils have enhanced bactericidal activities at inflammatory sites when TNF-α, C5adesArg, or both are produced locally. (Am J Vet Res 2000;61:951–959)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To elucidate tissue inhibitor of metalloproteinase (TIMP)-mediated effects on chondrocytes.

Sample Population—Articular cartilage from humeral heads of 6 dogs.

Procedure—Chondrocytes from harvested specimens were cultured in 3-dimensional (3-D) agarose at 106 cells/mL. We prepared 3-D constructs exposed to only tumor necrosis factor (TNF)-α (50 ng/mL). Recombinant human TIMP-1 (255nM), -2 (285nM), or -3 (250nM) was added to liquid media bathing 3-D constructs cultured with TNF-α. Chondrocytes cultured without TIMP or TNF-α served as control samples. Samples of liquid media were collected on days 6, 9, 15, and 21 of culture for evaluation of glycosaminoglycan (GAG) and nitric oxide concentrations. The 3-D constructs were collected on days 9, 15, and 21 for evaluation of GAG, hydroxyproline (HP), and DNA contents.

Results—GAG content in control samples increased significantly during the study, whereas GAG content in 3-D constructs cultured with TNF-α or TNF-α plus TIMP did not increase. On day 9, GAG release from 3-D constructs cultured with TNF-α was significantly higher than that in other constructs. The HP content in control samples increased during the study and was significantly higher than that in all other constructs on day 21. Concentrations of nitric oxide were significantly lower in control samples on day 6, compared with concentrations for all other constructs.

Conclusions and Clinical Relevance—Addition of TIMPs did not counteract suppression of GAG and HP accumulation in 3-D constructs exposed to TNF-α. Apparently, adverse effects on chondrocytes exposed to TNF-α cannot be prevented by addition of TIMP alone. (Am J Vet Res 2004;65:1611–1615)

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in American Journal of Veterinary Research

Summary

We examined the effect of infusion of lipopolysaccharide (lps) on serum tumor necrosis factor alpha (tnfα) concentration and clinical attitude in 2- to 3-day-old colostrum-fed (cf) and colostrum-deprived (cd) foals. Eleven cf and 8 cd neonatal foals were given a bolus IV infusion of Escherichia coli O55:B5 lipopolysaccharide (0.5 µg kg of body weight) in sterile saline (0.9% NaCl) solution. Four cf and 2 cd foals were given saline solution alone. Serum IgG concentration and serum anti-lps IgG(T) antibody titer were determined for each foal prior to infusion. A depression index was used to score clinical abnormalities. Serum tnfα concentration was estimated by use of an in vitro cytotoxicity bioassay that used WEHI 164 clone 13 cells as targets. The cytotoxic serum factor was identified as tnfα by immunoprecipitation with caprine antisera raised against the 15 NH2- terminal amino acids of human tnfα. Tumor necrosis factor alpha was not detected in any preiniusion serum samples nor in any samples from foals given saline solution alone. Serum tnfα concentration increased in all lps-infused foals and peaked between 60 and 90 minutes after infusion. Serum tnfα concentrations, expressed as mean percentage of peak serum tnfα concentration, persisted longer in cd foals given lps than in cf foals given lps. All lps-infused foals displayed clinical signs of endotoxemia, but mean depression index scores of the cf and cd foals given lps were not significantly different at any time. Serum tnfα concentrations were correlated with depression index scores in both lps-infused groups. Mean rectal temperature increased by 1 hour and remained high for 4 hours after infusion in cf foals given lps . Mean rectal temperature in cd foals given lps was significantly less than that for cf foals given lps 1 and 2 hours after infusion and was higher than mean rectal temperature prior to infusion 3 and 4 hours after infusion. Neither preinfusion total serum IgG concentration nor serum anti-lps IgG(T) antibody titer correlated with peak serum tnfα concentration in the 19 lps-infused foals.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine the capacity of inflammatory mediators tumor necrosis factor-α (TNF-α), interleukin- 8 (IL-8), platelet-activating factor (PAF), lipopolysaccharide (LPS), and leukotoxin to prime, activate, or alter deformability of adult bovine neutrophils.

Sample Population—Blood collected from 5 healthy adult Holstein cows.

Procedure—Isolated neutrophils or whole blood was incubated with TNF-α, IL-8, PAF, LPS, or leukotoxin, and neutrophil chemiluminescence, degranulation, deformability, shape change, CD11b expression, and size distribution was measured.

Results—Incubation with TNF-α, IL-8, PAF, and LPS primed neutrophils for oxygen radical release but caused minimal oxygen radical release by themselves. None of the inflammatory mediators induced degranulation. Incubation with TNF-α and PAF resulted in a decrease in neutrophil deformability and induced shape change in neutrophils. Incubation with PAF consistently resulted in an increase in neutrophil size as measured by use of flow cytometry. Only IL-8 caused an increase in expression of CD11b by neutrophils.

Conclusions and Clinical Relevance—Inflammatory mediators tested had minimal effects on neutrophil oxygen radical production or degranulation but did prime neutrophils for oxygen radical production. Incubation with PAF and TNF-α caused a decrease in neutrophil deformability and altered neutrophil shape and size. Results of our study indicate that PAF- and TNF-α-induced changes in neutrophil deformability and size may cause integrin- and selectin-independent trapping of neutrophils in the lungs of cattle with pneumonic pasteurellosis. ( Am J Vet Res 2000;61: 492–498)

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in American Journal of Veterinary Research

Summary

Objectives of this investigation were to extract and isolate protein fractions inhibitory to the cytotoxic properties of tumor necrosis factor-α (tnf-α). In this context, mixed populations of wbc were harvested from equine blood and were stimulated with a combination of a synthetic chemotactic peptide and a calcium ionophore. Several methods were subsequently applied for the initial preparation of cell-free crude protein extracts, including fractional precipitation with gradient concentrations of ammonium sulfate and preparative-scale isoelectric focusing. In addition, protein fractions were harvested from extracts of concentrated equine urine. Protein extracts of urinary origin were further separated by gel-filtration column chromatography.

Identification of protein fractions possessing properties inhibitory to the cytotoxic characteristics of tnf-α was facilitated by a tissue culture-based technique for the biological assay of tnf-α-mediated cytotoxicity. Purified protein extracts possessed a marked ability to inhibit or neutralize the cytotoxic properties of tnf-α, on the basis of survival of murine fibrosarcoma cell populations, compared with appropriate negative and positive reference controls. Relative purity of inhibitors and estimation of approximate molecular weight were established by conventional reducing and nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis. Equine inhibitory protein fractions from mixed wbc populations, purified in the manner described, had molecular weights of 70,000 to 80,000 and 28,000. An analogous protein fraction of 28 kDa also was isolated from equine concentrated urine. Estimated isoelectric point of tnf-α inhibitor protein fractions was between pH of 5.5 and 6.1. These physical characteristics of equine tnf-α inhibitor protein fractions were similar to those described for a membrane-associated tnf-α receptor protein shed from chemotaxin- and calcium-ionophor-stimulated human wbc populations.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine messenger RNA expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and interleukin- (IL)-1β from cultured equine smooth muscle cells (SMC).

Sample Population—Segments of palmar digital artery harvested from 6 clinically normal adult horses.

Procedure—Explants were collected from the tunica media of arteries for primary culture of SMC. Equine mononuclear cells were used as control cells. Subcultured vascular SMC and control cells were exposed to lipopolysaccharide (20 µg/ml and 100 ng/ml, respectively). Northern blot analysis with equine-specific probes for COX-2, TNF-α, and IL-1β was performed, using isolated total cellular RNA.

Results—Although no message was detected for IL-1β or TNF-α in control or endotoxin-exposed equine vascular SMC from all horses, COX-2 underwent a distinct substantial up-regulation after endotoxin exposure. Endotoxin-exposed equine mononuclear cells had up-regulation of IL-1β and TNF-α mRNA.

Conclusions and Clinical Relevance—Increased expression of COX-2 mRNA by equine vascular SMC may be an important early pathophysiologic event in the onset of endotoxemia in horses. Potentiated local vascular production of various prostanoids after increased expression of mRNA for COX-2 may result in vasoactive events observed with laminitis. (Am J Vet Res 2001;62:1957–1963)

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in American Journal of Veterinary Research