Residual effects of intra-articular betamethasone and triamcinolone acetonide in an equine acute synovitis model.

BACKGROUND: Intra-articular (IA) corticosteroids are regularly used in equine athletes for the control of joint inflammation. OBJECTIVES: The goal of this study was to use an acute synovitis inflammation model to determine the residual effects of IA betamethasone and triamcinolone acetonide on various inflammatory parameters and lameness. STUDY DESIGN: Crossover randomised trial. METHODS: Five mixed-breed, 2-year-old horses were randomly allocated to an IA treatment of the radiocarpal joint with 9 mg of either betamethasone or triamcinolone acetonide. Two weeks following treatment, horses were injected with 1 µg of lipopolysaccharide (LPS) diluted in 1 ml of saline. Following LPS injection, horses were crossed-over and both sets of injections were repeated after a washout period. Blood samples were collected at multiple time points for mRNA analysis, as well as serum amyloid A (SAA) and cortisol determination. At each time point, lameness was also subjectively scored. Additional injections with saline-only or LPS-only (twice) were conducted as negative and positive controls, respectively. Two-way repeated measures analysis of variance was used to analyse all data. RESULTS: Corticosteroid-only treatments result in significant mRNA expression differences, as well as significant and prolonged cortisol suppression. Following LPS injection, there was a residual treatment effect with triamcinolone evidenced by a significant treatment effect on IL-6 and PTGS1 (cyclooxygenase-1), lameness, SAA and cortisol concentrations, while only IL-6 expression was affected by betamethasone. MAIN LIMITATIONS: The acute synovitis model used here results in significant inflammation and is not representative of the low-grade inflammation seen with typical joint disease and residual anti-inflammatory effects may be more profound in naturally occurring joint disease. CONCLUSIONS: Current regulatory guidelines may be insufficient if the concern is residual anti-inflammatory effects. Additionally, intra-articular corticosteroid administration is not without risk, as evidenced by a significant suppression of serum cortisol concentration and, as such, the benefits of their administration should be weighed against those risks.

Effects of intravenous administration of peripheral blood-derived mesenchymal stromal cells after infusion of lipopolysaccharide in horses.

BACKGROUND: A systemic and dysregulated immune response to infection contributes to morbidity and mortality associated with sepsis. Peripheral blood-derived mesenchymal stromal cells (PB-MSC) mitigate inflammation in animal models of sepsis. Allogeneic PB-MSC administered IV to horses is well-tolerated but therapeutic benefits are unknown. HYPOTHESIS: After IV lipopolysaccharide (LPS) infusion, horses treated with PB-MSC would have less severe clinical signs, clinicopathological abnormalities, inflammatory cytokine gene expression, and oxidative stress compared to controls administered a placebo. ANIMALS: Sixteen horses were included in this study. METHODS: A randomized placebo-controlled experimental trial was performed. Sixteen healthy horses were assigned to 1 of 2 treatment groups (1 × 109 PB-MSC or saline placebo). Treatments were administered 30 minutes after completion of LPS infusion of approximately 30 ng/kg. Clinical signs, clinicopathological variables, inflammatory cytokine gene expression, and oxidative stress markers were assessed at various time points over a 24-hour period. RESULTS: A predictable response to IV LPS infusion was observed in all horses. At the dose administered, there was no significant effect of PB-MSC on clinical signs, clinicopathological variables, or inflammatory cytokine gene expression at any time point. Antioxidant potential was not different between treatment groups, but intracellular ROS increased over time in the placebo group. Other variables that changed over time were likely due to effects of IV LPS infusion. CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of allogeneic PB-MSC did not cause clinically detectable adverse effects in healthy horses. The dose of PB-MSC used here is unlikely to exert a beneficial effect in endotoxemic horses.

Streptolysin-O/antibiotics adjunct therapy modulates site-specific expression of extracellular matrix and inflammatory genes in lungs of Rhodococcus equi infected foals.

The addition of streptolysin-O (SLO) to the standard antibiotics regimen was shown to be superior to antibiotics alone after experimental infection of foals with Rhodoccocus equi (R. equi). The objective of this study is to investigate this response by determining the site-specific expression of extracellular matrix (ECM) and inflammatory response genes in biopsy samples taken from three distinct lung regions of the infected foals. Twenty-four foals were challenged by intrabronchial instillation of R. equi and assigned to four treatment groups: SLO/antibiotics adjunct therapy, antibiotics-only therapy (7.5 mg/kg clarithromycin and 5 mg/kg rifampin), SLO-only, and saline-only treatments. Treatments were administered twice daily for 16 days unless symptoms progressed to the point where the foals needed to be euthanized. Gene expressions were determined using custom-designed equine real-time qPCR arrays containing forty-eight genes from ECM remodeling and inflammation pathways. A non-parametric Wilcoxon signed-rank test for independent samples was applied to two pairs of time-matched comparison groups, SLO/antibiotics vs. antibiotics-only and SLO-only vs. saline-only, to document the significant differences in gene expressions within these groups. Several genes, MMP9, MMP2, TIMP2, COL1A1, COL12A1, ITGAL, ITGB1, FN1, CCL2, CCL3, CXCL9, TNFα, SMAD7, CD40, IL10, TGFB1, and TLR2, were significantly regulated compared to the unchallenged/untreated control foals. The results of this study demonstrate that enhancement of clinical responses by SLO is consistent with the changes in expression of critical genes in ECM remodeling and inflammatory response pathways.