Immunomodulatory properties of gamithromycin and ketoprofen in lipopolysaccharide-challenged calves with emphasis on the acute-phase response

Abstract

Macrolide antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be modulators of the innate immune response, irrespectively of their antimicrobial and anti-inflammatory actions. Therefore, it was our objective to evaluate whether the macrolide gamithromycin (GAM) and the NSAID ketoprofen (KETO) attenuate the acute-phase response in calves, and whether their combined administration is beneficial due to synergistic and/or additive effects. To this end, both drugs, as well as their combination, were studied in a previously developed inflammation model, i.e., the induction of an acute-phase response by an intravenous lipopolysaccharide (LPS) challenge (0.5μg/kg body weight). Sixteen 4-week-old Holstein–Friesian calves were randomized into 4 groups: a positive control (+CONTR) group, receiving LPS but no pharmacological treatment (n=4) and a GAM (n=4), a KETO (n=4) and a GAM–KETO (n=4) group, receiving the respective drugs 1h prior to LPS administration. Clinical scoring and blood collection were performed at regular time points until 72h post LPS challenge. Plasma concentrations of the selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)), acute-phase protein (serum amyloid A (SAA)) and prostaglandin E2 (PGE2) were subsequently quantified. Pre-treatment with GAM had no effect in the inflammation model compared to the +CONTR group. KETO, on the other hand, completely inhibited depression, anorexia and fever. This remarkable influence was associated with a significant reduction of PGE2 synthesis by KETO, while the effect on TNF-α, IL-6 and SAA was not straightforward. The combined administration of GAM and KETO provided no synergistic or additive effects in this model, neither clinically nor regarding the studied inflammatory mediators. In conclusion, KETO entirely inhibited PGE2 synthesis, fever development and depression, while GAM did not exert any effect in this model. These results promote the concomitant use of an antimicrobial drug and a NSAID in the treatment of calf diseases associated with LPS, both to enhance clinical recovery and to improve animal welfare.