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

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 (0.5 µg/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 72 h 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.

Modifying the acute phase response of Jersey calves by supplementing milk replacer with omega-3 fatty acids from fish oil.

Fifty-one Jersey bull calves (5 +/- 1 d old) were assigned to 1 of 3 milk replacers to determine the effects of increasing doses of n-3 fatty acids from fish oil on the acute phase response after an endotoxin challenge. All calves were fed a 22.5% crude protein and 18% lipid milk replacer (Calva Products, Acampo, CA) supplemented with an additional 2% fatty acids. Treatments differed only in the supplemental lipid source and included a 3:1 mix of corn and canola oils, a 1:1 blend of fish oil (Omega Proteins, Houston, TX) and the 3:1 mix of corn and canola oils, and fish oil only. On d 23, each calf was injected subcutaneously with 4 microg/kg of body weight of Salmonella Typhimurium endotoxin. Clinical, hematological, and biochemical parameters were measured at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24, and 72 h post endotoxin challenge. Endotoxin caused a dramatic rise in respiratory rate; feeding fish oil significantly attenuated the increase. Heart rate and rectal temperature were not affected by treatment. Feeding fish oil attenuated the change in serum iron concentration over time. Endotoxin caused severe hypoglycemia, reaching a nadir at 4 h. Calves supplemented with fish oil had reduced concentrations of serum glucose for 8 to 24 h. Furthermore, calves supplemented with fish oil alone had reduced serum insulin at 12, 28, and 24 h. In contrast, endotoxin caused an acute increase in blood urea nitrogen and nonesterified fatty acids; there were significant linear effects of fish oil on both blood urea nitrogen and nonesterified fatty acids. Serum triglycerides were elevated beginning at 12 h after the endotoxin challenge and returned to baseline values within 72 h. Fish oil suppressed the rise in triglycerides during this period, and the effect was linear with increasing fish oil. Serum concentrations of leptin decreased after the endotoxin challenge; however, the treatment did not influence the response. There was no treatment effect on serum aspartate aminotransferase or lactate dehydrogenase activity. Adding fish oil to milk replacer attenuated many aspects of the acute phase response, and the effect was linear in the range of 5 to 10% of the lipid replaced as fatty acids from fish oil. Adding fish oil might provide a better balance between a necessary versus an excessive acute phase response.

Modulation by enteral nutrition of the acute phase response and immune functions.

To use nutrition in order to limit the negative consequences of physical and mental stress is not new. Recent advances in immunology and particularly in the understanding of the chemical language used to communicate both by eukarytic and prokarotic cells has made it easier to objectively evaluate effects of various immunomodulating efforts including the use of nutrients, vitamins and antioxidants in preventing or limiting the development of disease and its late consequences.

Reduced inflammatory response in rats fed fat-rich diets: role of leukotrienes.

The effect of fat-rich diets on the acute inflammatory response was examined. Male Wistar rats aged 21 days were fed, for 6 weeks, with a control diet (4% fat content), or a control diet supplemented with coconut or soybean oils (15% fat content). Carrageenan-induced paw oedema and pleurisy were evaluated. Prostaglandin (PG) E2 and leukotriene (LT) C4/D4 concentrations were determined in the pleural exudate (ELISA). Pleural samples were tested for their effect on cutaneous vascular permeability of control rats and the effect of a LTD4 receptor antagonist (L660-711; 10 mg/kg; i.v.) examined. Relative to controls, rats fed both fat-rich diets presented a significant reduction in protein leakage and oedema formation without affecting the number of migrating leukocytes. Production of LTC4/D4 in pleural exudate was significantly increased from 1.8 +/- 0.2 ng/ml in controls to 2.8 +/- 0.2 and 3.0 +/- 0.3 ng/ml in animals fed coconut and soybean oil enriched diets, respectively, without changes in PGE2 production. The activity of these samples on cutaneous vascular permeability was 50% reduced, returning to control values after treatment of testing animals with a LTD4 receptor antagonist. Rats fed fat-rich diets presented a reduced inflammatory response due, at least in part, to the LTC4/D4 mediated vasoconstrictor effect.