Lorraine M. Sordillo

Impact of oxidative stress on the health and immune function of dairy cattle.

Oxidation and the production of free radicals are an integral part of aerobic metabolism. A variety of reactive oxygen species (ROS) are produced by normal metabolic processes and by certain leukocyte populations during defense against disease. Accumulated scientific evidence supports the concept that oxidative damage of tissues and cellular components are either a primary or secondary cause of many human diseases. Unfortunately, considerably less is known about how oxidative stress can affect veterinary health and well-being, particularly during times of high metabolic activity. The performance of high producing dairy cattle can be optimized to a certain extent by supplementing diets with optimal levels of micronutrients with antioxidant capabilities. However, oxidative stress continues to be a problem in transition cows. Innovative approaches are needed to enhance the antioxidant defense mechanisms of dairy cattle during times of increased metabolic demands.

Metabolic factors affecting the inflammatory response of periparturient dairy cows

Abstract Dairy cattle are susceptible to increased incidence and severity of disease during the periparturient period. Increased health disorders have been associated with alterations in bovine immune mechanisms. Many different aspects of the bovine immune system change during the periparturient period, but uncontrolled inflammation is a dominant factor in several economically important disorders such as metritis and mastitis. In human medicine, the metabolic syndrome is known to trigger several key events that can initiate and promote uncontrolled systemic inflammation. Altered lipid metabolism, increased circulating concentrations of non-esterified fatty acids and oxidative stress are significant contributing factors to systemic inflammation and the development of inflammatory-based diseases in humans. Dairy cows undergo similar metabolic adaptations during the onset of lactation, and it was postulated that some of these physiological events may negatively impact the magnitude and duration of inflammation. This review will discuss how certain types of fatty acids may promote uncontrolled inflammation either directly or through metabolism into potent lipid mediators. The relationship of increased lipid metabolism and oxidative stress to inflammatory dysfunction will be reviewed as well. Understanding more about the underlying cause of periparturient health disorders may facilitate the design of nutritional regimens that will meet the energy requirements of cows during early lactation and reduce the susceptibility to disease as a function of compromised inflammatory responses.

Significance of Metabolic Stress, Lipid Mobilization, and Inflammation on Transition Cow Disorders

The incidence and severity of disease in cows is greatest during the transition period, when immune functions are impaired. Intense lipid mobilization is associated with both metabolic and infectious diseases in the transition cow. Significant increases in plasma nonesterified fatty acids contribute to oxidative stress and uncontrolled inflammatory responses. A dysfunctional inflammatory response is the common link between metabolic and infectious diseases around the time of calving. Intervention strategies that can reduce lipid mobilization may improve inflammatory responses and reduce the economic losses associated with health disorders during the transition period.

Lipid mobilization and inflammatory responses during the transition period of dairy cows

The transition period of dairy cattle is characterized by dramatic changes in metabolism and host defense mechanisms that are associated with increased disease. Intense lipid mobilization from tissue stores is an important metabolic adaptation during the transition period that results in significant release of non-esterified fatty acids (NEFA) into the blood stream. Whereas these fatty acids are important sources of energy during times of increased metabolic demands, elevated concentrations of NEFA are known to disrupt several immune and inflammatory functions. This review will discuss the implications of lipid mobilization on inflammatory responses with special emphasis on leukocytes and endothelial cell functions during the transition period of dairy cows.

Immunopathology of Mastitis: Insights into Disease Recognition and Resolution

Mastitis is an inflammation of the mammary gland commonly caused by bacterial infection. The inflammatory process is a normal and necessary immunological response to invading pathogens. The purpose of host inflammatory responses is to eliminate the source of tissue injury, restore immune homeostasis, and return tissues to normal function. The inflammatory cascade results not only in the escalation of local antimicrobial factors, but also in the increased movement of leukocytes and plasma components from the blood that may cause damage to host tissues. A precarious balance between pro-inflammatory and pro-resolving mechanisms is needed to ensure optimal bacterial clearance and the prompt return to immune homeostasis. Therefore, inflammatory responses must be tightly regulated to avoid bystander damage to the milk synthesizing tissues of the mammary gland. The defense mechanisms of the mammary gland function optimally when invading bacteria are recognized promptly, the initial inflammatory response is adequate to rapidly eliminate the infection, and the mammary gland is returned to normal function quickly without any noticeable clinical symptoms. Suboptimal or dysfunctional mammary gland defenses, however, may contribute to the development of severe acute inflammation or chronic mastitis that adversely affects the quantity and quality of milk. This review will summarize critical mammary gland defense mechanisms that are necessary for immune surveillance and the rapid elimination of mastitis-causing organisms. Situations in which diminished efficiency of innate or adaptive mammary gland immune responses may contribute to disease pathogenesis will also be discussed. A better understanding of the complex interactions between mammary gland defenses and mastitis-causing pathogens should prove useful for the future control of intramammary infections.

Lipomobilization in periparturient dairy cows influences the composition of plasma nonesterified fatty acids and leukocyte phospholipid fatty acids

The periparturient period is characterized by sudden changes in metabolic and immune cell functions that predispose dairy cows to increased incidence of disease. Metabolic changes include alterations in the energy balance that lead to increased lipomobilization with consequent elevation of plasma nonesterified fatty acids (NEFA) concentrations. The objective of this study was to establish the influence of lipomobilization on fatty acid profiles within plasma lipid fractions and leukocyte phospholipid composition. Blood samples from 10 dairy cows were collected at 14 and 7 d before due date, at calving, and at 7, 14, and 30 d after calving. Total lipids and lipid fractions were extracted from plasma and peripheral blood mononuclear cells. The degree of lipomobilization was characterized by measurement of plasma NEFA concentrations. The fatty acid profile of plasma NEFA, plasma phospholipids, and leukocyte phospholipids differed from the composition of total lipids in plasma, where linoleic acid was the most common fatty acid. Around parturition and during early lactation, the proportion of palmitic acid significantly increased in the plasma NEFA and phospholipid fractions with a concomitant increase in the phospholipid fatty acid profile of leukocytes. In contrast, the phospholipid fraction of long-chain polyunsaturated fatty acids in leukocytes was diminished during the periparturient period, especially during the first 2 wk following parturition. This study showed that the composition of total plasma lipids does not necessarily reflect the NEFA and phospholipid fractions in periparturient dairy cows. These findings are significant because it is the plasma phospholipid fraction that contributes to fatty acid composition of membrane phospholipids. Increased availability of certain saturated fatty acids in the NEFA phospholipid fractions may contribute to altered leukocyte functions during the periparturient period.

Thioredoxin reductase regulates the induction of haem oxygenase-1 expression in aortic endothelial cells

Certain selenoproteins such as GPX-1 (glutathione peroxidase-1) and TrxR1 (thioredoxin reductase-1) possess important antioxidant defence functions in vascular endothelial cells. Reduced selenoprotein activity during dietary selenium (Se) deficiency can result in a compensatory increase of other non-Se-dependent antioxidants, such as HO-1 (haem oxygenase-1) that may help to counteract the damaging effects of oxidant stress. However, the role of individual selenoproteins in regulating vascular-derived protective gene responses such as HO-1 is less understood. Using an oxidant stress model based on Se deficiency in BAECs (bovine aortic endothelial cells), we sought to determine whether TrxR1 activity may contribute to the differential regulation of HO-1 expression as a function of altered redox environment. Se-sufficient BAECs up-regulated HO-1 expression following stimulation with the pro-oxidant, 15-HPETE (15-hydroperoxyeicosatetraenoic acid), and levels of this antioxidant inversely correlated with EC apoptosis. While Se-deficient BAECs exhibited higher basal levels of HO-1, it was not up-regulated upon 15-HPETE treatment, which resulted in significantly higher levels of pro-apoptotic markers. Subsequent results showed that HO-1 induction depended on the activity of TrxR1, as proved with chemical inhibitor studies and direct inhibition with TrxR1 siRNA. Finally, restoring intracellular levels of the reduced substrate Trx (thioredoxin) in Sedeficient BAECs was sufficient to increase HO-1 activation following 15-HPETE stimulation. These data provide evidence for the involvement of the Trx/TrxR system, in the regulation of HO-1 expression in BAECs during pro-oxidant challenge.

Dietary Polyunsaturated Fatty Acids and Inflammation: The Role of Phospholipid Biosynthesis

The composition of fatty acids in the diets of both human and domestic animal species can regulate inflammation through the biosynthesis of potent lipid mediators. The substrates for lipid mediator biosynthesis are derived primarily from membrane phospholipids and reflect dietary fatty acid intake. Inflammation can be exacerbated with intake of certain dietary fatty acids, such as some ω-6 polyunsaturated fatty acids (PUFA), and subsequent incorporation into membrane phospholipids. Inflammation, however, can be resolved with ingestion of other fatty acids, such as ω-3 PUFA. The influence of dietary PUFA on phospholipid composition is influenced by factors that control phospholipid biosynthesis within cellular membranes, such as preferential incorporation of some fatty acids, competition between newly ingested PUFA and fatty acids released from stores such as adipose, and the impacts of carbohydrate metabolism and physiological state. The objective of this review is to explain these factors as potential obstacles to manipulating PUFA composition of tissue phospholipids by specific dietary fatty acids. A better understanding of the factors that influence how dietary fatty acids can be incorporated into phospholipids may lead to nutritional intervention strategies that optimize health.

Evaluation of antioxidant and proinflammatory gene expression in bovine mammary tissue during the periparturient period

The incidence and severity of mastitis can be high during the period of transition from pregnancy to lactation when dairy cattle are susceptible to oxidative stress. Oxidative stress may contribute to the pathogenesis of mastitis by modifying the expression of proinflammatory genes. The overall goal of this study was to determine the relationship between critical antioxidant defense mechanisms and proinflammatory markers in normal bovine mammary tissue during the periparturient period. Mammary tissue samples were obtained from 12 cows at 35, 20, and 7 d before expected calving and during early lactation (EL, 15 to 28 d in milk). Enzyme activities for cytosolic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase were relatively low during the dry period, but increased during EL, whereas activity of thioredoxin reductase 1 did not change significantly as a function of time. In contrast, gene expression for these antioxidant selenoproteins and for heme oxygenase-1 gradually decreased as parturition approached and then increased during EL. The expression of intercellular vascular adhesion molecule-1 and vascular cell adhesion molecule-1 followed a similar trend where mRNA abundance gradually declined as parturition approached with a slight rebound in EL. Gene expression of the pro-oxidant, 15-lipoxygenase 1, which is known to increase during times of oxidative stress, also increased dramatically in mammary tissue from EL cows. Expression of the proinflammatory cytokines, IL-1beta, IL-6, and IL-8 did not change significantly during the periparturient period. Strong positive correlations were found between several antioxidant enzymes (cytosolic glutathione peroxidase, thioredoxin reductase 1, and heme oxygenase-1) and vascular adhesion molecules (intercellular vascular adhesion molecule-1, vascular cell adhesion molecule-1) suggesting a protective response of these antioxidants to an enhanced proinflammatory state. Ability to control oxidative stress through manipulation of key antioxidant enzymes in the future may modify the proinflammatory state of periparturient cows and reduce incidence and severity of some diseases such as mastitis.

Selenium-Dependent Regulation of Oxidative Stress and Immunity in Periparturient Dairy Cattle

Uncontrolled or impaired immune and inflammatory responses in periparturient dairy cows are associated with increased incidence and severity of infectious diseases. The progressive development of oxidative stress during the transition from late gestation to peak lactation is thought to be a significant underlying factor leading to dysfunctional immune cell responses. Certain trace minerals, such as selenium (Se), can ameliorate oxidative stress and reduce the severity of several economically important diseases in dairy cattle including mastitis and metritis. Many of the health benefits of Se can be attributed to the antioxidant functions of selenoproteins. Changes in selenoprotein activity as a consequence of Se nutritional status can directly alter a number of critical cellular functions involved in the inflammatory response. A better understanding of how Se can optimize immune cell responses may facilitate the design of nutritional regimes that will reduce health disorders during the periparturient period.