Critical control points in the impact of the proinflammatory immune response on growth and metabolism1,2

Abstract

Intrinsic in the equation for successful animal production is the efficiency of nutrient use for assimilation into useful animal-derived products. However, when young growing animals encounter various stressors that activate the proinflammatory response (PR), the biochemical effects of the resulting cascade of PR mediators [cytokines, prostaglandin and prosta-cyclin derivatives, nitric oxide (NO), superoxide anion (O2(.-)), etc.] override the regulatory signals normally ascribed to anabolic tissue accretion and growth. The efficiency of energy and nutrient use will proportionally decrease for growth rate due to the redirection of nutrient use to support immune defense processes. These proinflammatory events can develop in association with infectious disease but also are apparent in and a part of the natural response to birth, parturition, and weaning. If growth patterns are tracked during the PR, growth deficits are often apparent. Some growth deficits are relatively transient in duration, whereas others are quite long lasting, persisting although traditional clinical markers of PR are no longer evident. Recent evidence indicates that the PR cascades initiated by cytokines like tumor necrosis factor-alpha play a major role in these growth deficits. Perturbations in mitochondrial energetics and NO and O2(.-) interactions further affect metabolic balance. Free radicals and reactive nitrogen intermediates interact with select molecular targets in proteins (i.e., enzymes, histone proteins, and signal transduction proteins), causing the nitration and nitrosylation of select amino acids. If these posttranslational modifications occur in proteins associated with control points critical in metabolic stability, the resulting altered protein structure blocks its functionality. Attenuation of these overt posttranslational protein modifications at their site of production offers a strategy to minimize their detrimental impact while preserving needed cytokine, NO, and O2(.-) functions.

Biomarker responses to weaning stress in beef calves

“…those required for survival, e.g. an immune response) (Elsasser et al, 1997(Elsasser et al, , 2008. Furthermore, intake and appetite are suppressed during stressful events (Haddad et al, 2002) with intake of nutrients by stressed livestock often compromised and below that normally consumed by unstressed animals (Duff and Galyean, 2007).…”

Short-term alpha- or gamma-delta-enriched tocopherol oil supplementation differentially affects the expression of proinflammatory mediators: selective impacts on characteristics of protein tyrosine nitration in vivo

“…The calf was used as an animal model because of its greater sensitivity to LPS than rodent models and because many of the responses are similar to those observed in human low-level endotoxicosis, 6,28 and in particular, because of the paucity of data in cattle describing tissue and plasma content of non-α-isoforms in states of health or proinflammatory stress. The dose of LPS chosen here is consistent with the dose used many times previously in our laboratory, a dose that results in short-term febrile response and fever, minor depression in feed intake, increased generation of liver nitrated proteins and followed by recovery.…”

“…35,36 Finally, we used this particular model and target tissue because of its capacity to a) address the need to mitigate the impact of disease stress on animals and humans, b) suggest cost-effective alternatives and adjuncts as a therapy largely without conventional drug residue issues, c) provides through feeding a practical and noninvasive route of administration, d) ensures distribution to the liver via the portal route from the digestive track and e) exploits the value of tyrosine nitration as a biomarker of nitrooxidative stress that has been well characterized in our laboratory in similar proinflammatory models of disease. 6,20,21,[27][28][29] There are two critical levels at which modulation of nitration can be effected: first, via altered generation of the ONOO -forming reactants NO and/or O2• -and second, decreasing the probability of interaction of ONOO-with impact targets such as tyrosine residues. Data suggest that inhibition of NO and/or O2• -is equivocal and problematic in regard to morbidity and mortality of clinical outcomes.…”

“…6,21 The vast majority of domestic animal applications of tocopherol supplementation in the other mentioned applications were based on the use of a synthetic acetate or succinate form. Furthermore, in many citations in which the plasma or tissue levels of tocopherol were evaluated, it was only the α-isoform measured or reported, to the exclusion of the γ-isoform and thus the present paper constitutes a first report of comparative tocopherol isoforms measured in plasma and liver, as affected by short-term feeding and further impacted by the inflammatory character of LPS challenge.…”

“…14,15 Our laboratory described previously several perturbations in liver function that were strongly associated with a proinflammatory induction of generalized as well as specific signal transduction-related protein tyrosine nitration responses in calf liver. 6,19,21 In light of our results and the biological impact of ONOOreported by others, we considered the potential to modulate the reactivity of ONOO -an achievable goal in the attempt to mitigate some of the possible negative attributes of nitrooxidative stress arising from both mitochondrial and cytosolic perturbations. Key to resolving this is targeting for remediation those impact points that have the greatest benefit with the least collateral impact on the nitric oxide and superoxide anion generating pathways.…”