Effect of intravenous lipid and glutathione infusions on metabolism, inflammation, and immune functions of dairy cows

During the transition period, dairy cows often present metabolic and immunological disturbances. For several years, negative energy balance and the associated increase in blood nonesterified fatty acids (NEFA) have been considered the most likely causes of these disturbances. However, the transition period is also associated with a state of systemic inflammation. Some recent studies suggest that this inflammation is the result of a leakage of LPS from the intestines, uterus, and mammary gland into the blood compartment and that metabolic and immune disturbances are the consequences. As it is difficult to determine the exact contribution of NEFA to these disturbances during the transition period, we had previously developed an experimental model to evaluate the effect of NEFA on metabolic disturbances and immune functions independently of energy balance, as well as of hormonal and physiological changes due to parturition. In the present study, we used this model to evaluate the effect of NEFA and glutathione (GSH), a substance that counteracts the action of NEFA on lymphocyte proliferation in vitro. Six dry, nonpregnant cows were used in a 3 × 3 double Latin square experiment. In the control treatment, cows received an intravenous infusion of saline for 6 h. In the other 2 treatments, cows were infused with a lipid emulsion (Intralipid 20%, Fresenius Kabi) at a rate of 1 mL/kg BW per hour for 6 h. Three hours after the start of Intralipid infusion, cows were also infused with saline (control and lipid treatments) or GSH (60 mg/kg BW over 5 min; lipid + GSH treatment). Blood samples were collected before, during, and after the infusions for the determination of metabolites, hormones, acute-phase proteins, cytokines, and lymphocyte proliferation. The GSH infusion had only a marginal effect on its serum concentration, and the results of lipid + GSH treatment did not differ from the lipid treatment on any other measured parameters. Intralipid infusion caused an ∼18-fold increase in serum NEFA concentration, reaching values ​​(>850 ± 56 µM) similar to those observed in early lactation. Similarly, serum BHB concentration doubled following Intralipid infusion. Intralipid infusion caused a significant increase in serum glucose and insulin levels, suggesting that NEFA are responsible for the insulin resistance frequently observed in the peripartum period. Intralipid infusion caused an increase in the serum levels of several cytokines, including IL-6, IL-10, IFN-γ-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory proteins-1α and -1β, and vascular endothelial growth factor. It also decreased the concentration of the IL-36 receptor antagonist. Cortisol was also increased by Intralipid infusion. Serum levels of the acute-phase proteins haptoglobin and serum amyloid A were also significantly increased (>20-fold) following Intralipid infusion, but this was only at the 24-h time point (18 h after the end of the infusion). Lymphocyte proliferation tended to be reduced after 6 h of Intralipid infusion. Results from the present study demonstrate that IV infusion of triglyceride emulsions increases NEFA, BHB, and inflammatory markers, alters cytokine profiles, and causes insulin resistance in a nonlactating bovine model of dyslipidemia. Although these results were obtained with a short-term dry cow experimental model, they further support the hypothesis that an increase in blood NEFA concentration is at least partially responsible for the reduction of peripheral blood mononuclear cell proliferation, inflammation, and insulin resistance associated with the transition period.