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In vitro effects of poly(ADP-ribose) polymerase inhibitors on the production of tumor necrosis factor-α by interferon- γ – and lipopolysaccharide-stimulated peripheral blood mononuclear cells of horses

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  • 1 1Dipartimento di Scienze Veterinarie, Università degli Studi di Torino, Grugliasco, TO, Italy.
  • | 2 2Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania, PA 19104.
  • | 3 3Department of Clinical Studies–New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.

Abstract

OBJECTIVE

To evaluate effects of poly(ADP-ribose) polymerase-1 (PARP1) inhibitors on the production of tumor necrosis factor-α (TNF-α) by interferon-γ (IFN-γ)– and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) of horses as an in vitro model of inflammation in horses.

SAMPLE

1,440 samples of PBMCs from 6 healthy research horses.

PROCEDURES

From heparinized whole blood samples, PBMC cultures were obtained. An initial dose-response trial on 48 PBMC samples from 2 horses (24 samples each) was used to determine concentrations of IFN-γ and LPS for use as low- and high-level stimulation concentrations. Seventy-two PBMC samples from 6 horses were assigned equally to 1 of 4 PARP1 inhibition categories: no PARP1 inhibitor (PARP1 inhibition control); 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carbozamide dihydrochloride (ABT888);4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (AZD2281); or N-(6-oxo-5,6-dihydrophenanthridin-2-yl) -N,N-dimethylacetamide hydrochloride (PJ34). Samples of PBMCs from each horse and each PARP1 inhibition category were then assigned to 1 of 3 levels of IFN-γ and LPS stimulation: none (control), low stimulation, or high stimulation. After a 24-hour incubation period, a TNF-α ELISA was used to measure TNF-α concentration in the supernatant. Results were compared across treatments and for each horse. Data were analyzed with repeated-measures ANOVA.

RESULTS

Median TNF-α concentration was significantly lower for PJ34-treated, high-level stimulated PBMCs than for PARP1 inhibition control, high-level stimulated PBMCs; however, no other meaningful differences in TNF-α concentration were detected among the inhibition and stimulation combinations.

CONCLUSIONS AND CLINICAL RELEVANCE

Findings suggested that PJ34 PARP1 inhibition may reduce TNF-α production in horses, a potential benefit in reducing inflammation and endotoxin-induced damage in horses.

Contributor Notes

Drs. Meyer-Ficca and Meyer's present address is Department of Animal, Dairy, and Veterinary Sciences, School of Veterinary Medicine, Utah State University, Logan, UT 84322.

Drs. Cacciolatti and Zarucco contributed equally to the study.

Address correspondence to Dr. Zarucco (laura.zarucco@unito.it).