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Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions., (© 2018 S. Karger AG, Basel.)

The discovery of vitamin E will have its 100th anniversary in 2022, but we still have more questions than answers regarding the biological functions and the essentiality of vitamin E for human health. Discovered as a factor essential for rat fertility and soon after characterized for its properties of fat-soluble antioxidant, vitamin E was identified to have signaling and gene regulation effects in the 1980s. In the same years the cytochrome P-450 dependent metabolism of vitamin E was characterized and a first series of studies on short-chain carboxyethyl metabolites in the 1990s paved the way to the hypothesis of a biological role for this metabolism alternative to vitamin E catabolism. In the last decade other physiological metabolites of vitamin E have been identified, such as α-tocopheryl phosphate and the long-chain metabolites formed by the ω-hydroxylase activity of cytochrome P-450. Recent findings are consistent with gene regulation and homeostatic roles of these metabolites in different experimental models, such as inflammatory, neuronal and hepatic cells, and in vivo in animal models of acute inflammation. Molecular mechanisms underlying these responses are under investigation in several laboratories and side-glances to research on other fat soluble vitamins may help to move faster in this direction. Other emerging aspects presented in this review paper include novel insights on the mechanisms of reduction of the cardiovascular risk, immunomodulation and antiallergic effects, neuroprotection properties in models of glutamate excitotoxicity and spino-cerebellar damage, hepatoprotection and prevention of liver toxicity by different causes and even therapeutic applications in non-alcoholic steatohepatitis. We here discuss these topics with the aim of stimulating the interest of the scientific community and further research activities that may help to celebrate this anniversary of vitamin E with an in-depth knowledge of its action as vitamin., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Asthma occurs as complex interactions of the environmental and genetics. Clinical studies and animal models of asthma indicate dietary factors such as vitamin E and vitamin D as protective for asthma risk. In this review, we discuss opposing regulatory functions of tocopherol isoforms of vitamin E and regulatory functions of vitamin D in asthma and how the variation in global prevalence of asthma may be explained, at least in part, by these dietary components., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Asthma and allergic lung disease occur as complex environmental and genetic interactions. Clinical studies of asthma indicate a number of protective dietary factors, such as vitamin E, on asthma risk. However, these studies have had seemingly conflicting outcomes. In this perspective, we discuss opposing regulatory effects of tocopherol isoforms of vitamin E, mechanisms for tocopherol isoform regulation of allergic lung inflammation, association of vitamin E isoforms with outcomes in clinical studies, and how the variation in global prevalence of asthma may be explained, at least in part, by vitamin E isoforms.

Aims: ICAM-1-dependent leukocyte recruitment in vivo is inhibited by the vitamin E isoform d-α-tocopherol and elevated by d-γ-tocopherol. ICAM-1 is reported to activate endothelial cell signals including protein kinase C (PKC), but the PKC isoform and the mechanism for ICAM-1 activation of PKC are not known. It is also not known whether ICAM-1 signaling in endothelial cells is regulated by tocopherol isoforms. We hypothesized that d-α-tocopherol and d-γ-tocopherol differentially regulate ICAM-1 activation of endothelial cell PKC., Results: ICAM-1 crosslinking activated the PKC isoform PKCα but not PKCβ in TNFα-pretreated human microvascular endothelial cells. ICAM-1 activation of PKCα was blocked by the PLC inhibitor U73122, ERK1/2 inhibitor PD98059, and xanthine oxidase inhibitor allopurinol. ERK1/2 activation was blocked by inhibition of XO and PLC but not by inhibition of PKCα, indicating that ERK1/2 is downstream of XO and upstream of PKCα during ICAM-1 signaling. During ICAM-1 activation of PKCα, the XO-generated ROS did not oxidize PKCα. Interestingly, d-α-tocopherol inhibited ICAM-1 activation of PKCα but not the upstream signal ERK1/2. The d-α-tocopherol inhibition of PKCα was ablated by the addition of d-γ-tocopherol., Conclusions: Crosslinking ICAM-1 stimulated XO/ROS which activated ERK1/2 that then activated PKCα. ICAM-1 activation of PKCα was inhibited by d-α-tocopherol and this inhibition was ablated by the addition of d-γ-tocopherol. These tocopherols regulated ICAM-1 activation of PKCα without altering the upstream signal ERK1/2. Thus, we identified a mechanism for ICAM-1 activation of PKC and determined that d-α-tocopherol and d-γ-tocopherol have opposing regulatory functions for ICAM-1-activated PKCα in endothelial cells.

Vitamin E regulation of disease has been extensively studied in humans, animal models and cell systems. Most of these studies focus on the α-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E, especially with regards to clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with recently reported unrecognized properties of isoforms of vitamin E. Recently, it has been reported that physiological levels of purified natural forms of vitamin E have opposing regulatory functions during inflammation. These opposing regulatory functions by physiological levels of vitamin E isoforms impact interpretations of previous studies on vitamin E. Moreover, additional recent studies also indicate that the effects of vitamin E isoforms on inflammation are only partially reversible using physiological levels of a vitamin E isoform with opposing immunoregulatory function. Thus, this further influences interpretations of previous studies with vitamin E in which there was inflammation and substantial vitamin E isoforms present before the initiation of the study. In summary, this review will discuss regulation of inflammation by vitamin E, including alternative interpretations of previous studies in the literature with regards to vitamin E isoforms.

Reports indicate contradictory outcomes for anti-inflammatory functions of the alpha-tocopherol isoform of vitamin E in clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with novel unrecognized properties of isoforms of vitamin E reported in this study. We demonstrate that the isoform d-gamma-tocopherol elevates inflammation in experimental asthma. Moreover, d-gamma-tocopherol, at as little as 10% the concentration of d-alpha-tocopherol, ablates the anti-inflammatory benefit of the d-alpha-tocopherol isoform. A mechanism for these opposing immunoregulatory functions of purified tocopherols at physiological concentrations is not through modulation of expression of several cytokines, chemokines, or adhesion molecules, but is, at least in part, by regulation of endothelial cell signals during leukocyte recruitment. These opposing regulatory functions of vitamin E isoforms have impact on interpretations of vitamin E studies. In summary, our studies with purified tocopherol isoforms alter our understanding of vitamin E regulation of vascular function and asthma.

Asthma and allergic disease result from interactions of environmental exposures and genetics. Vitamin E is one environmental factor that can modify development of allergy early in life and modify responses to allergen after allergen sensitization. Seemingly varied outcomes from vitamin E are consistent with the differential functions of the isoforms of vitamin E. Mechanistic studies demonstrate that the vitamin E isoforms α-tocopherol and γ-tocopherol have opposite functions in regulation of allergic inflammation and development of allergic disease, with α-tocopherol having anti-inflammatory functions and γ-tocopherol having pro-inflammatory functions in allergy and asthma. Moreover, global differences in prevalence of asthma by country may be a result, at least in part, of differences in consumption of these two isoforms of tocopherols. It is critical in clinical and animal studies that measurements of the isoforms of tocopherols be determined in vehicles for the treatments, and in the plasma and/or tissues before and after intervention. As allergic inflammation is modifiable by tocopherol isoforms, differential regulation by tocopherol isoforms provide a foundation for development of interventions to improve lung function in disease and raise the possibility of early life dietary interventions to limit the development of lung disease. [Display omitted] • Increased prevalence of asthma/allergy and altered consumption of tocopherol isoforms. • α-tocopherol associates with better lung function but this is reduced by γ-tocopherol. • In mice, tocopherol isoforms regulate allergy in adults and their offspring. • α- and γ-tocopherol inhibit and enhance, respectively, protein kinase C activation. • Needed are studies for a basis to recommend daily tocopherol isoform doses in disease. [ABSTRACT FROM AUTHOR]

γ-Tocopherol increases responses to allergen challenge in allergic adult mice, but it is not known whether γ-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether γ-tocopherol augments development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with γ-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to allergen challenge. The γ-tocopherol supplementation of allergic female mice increased the numbers of eosinophils twofold in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also about a twofold increase in pup lung CD11b+ subsets of CD11c+ dendritic cells and in numbers of these dendritic cells expressing the transcription factor IRF4. There was no change in several CD11b- dendritic cell subsets. Furthermore, maternal supplementation with γ-tocopherol increased the number of fetal liver CD11b+ CD11c+ dendritic cells twofold in utero. In the pups, γ-tocopherol increased lung expression of the inflammatory mediators CCL11, amphiregulin, activin A, and IL-5. In conclusion, maternal supplementation with γ-tocopherol increased fetal development of subsets of dendritic cells that are critical for allergic responses and increased development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with γ-tocopherol in prenatal vitamins. [ABSTRACT FROM AUTHOR]

α-Tocopherol blocks responses to allergen challenge in allergic adult mice, but it is not known whether α-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether α-tocopherol blocked development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with α-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to the allergen challenge, and α-tocopherol supplementation of allergic female mice resulted in a dose-dependent reduction in eosinophils in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also a reduction in pup lung CD11b+ dendritic cell subsets that are critical to development of allergic responses, but there was no change in several CD11b- dendritic cell subsets. Furthermore, maternal supplementation with α-tocopherol reduced the number of fetal liver CD11b+ dendritic cells in utero. In the pups, there was reduced allergen-induced lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24. Cross-fostering pups at the time of birth demonstrated that α-tocopherol had a regulatory function in utero. In conclusion, maternal supplementation with α-tocopherol reduced fetal development of subsets of dendritic cells that are critical for allergic responses and reduced development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with α-tocopherol. [ABSTRACT FROM AUTHOR]

Background: Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness. Methods: To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA. Results: In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175-545 ml lower FEV1 and FVC at ages 21-55 years. Conclusion: Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population. [ABSTRACT FROM AUTHOR]