Two faces of vitamin e in the lung.

To the Editor: The hypothesis for tocopherol isoform-dependent effects on asthma prevalence by Cook-Mills and colleagues (1) is derived in part from their important animal work, but also their interpretation of our own work with γ-tocopherol (γT) in experimental asthma. Although we have recently demonstrated that γT-enriched supplements can reduce endotoxin-induced neutrophil responses in human lung (2), we think the authors misinterpret our results in experimental asthma models when they conclude that γT was effective against neutrophilic, but not eosinophilic, inflammation. Both our results with antigen-induced asthma and rhinitis in rats (3) and ozone-induced exacerbation of allergic rhinitis (4) demonstrate 70–100% reduction in tissue or lavage eosinophils. We saw no effect of γT on any attendant neutrophil airway inflammation. Our results were also striking for the complete abolition by γT of mucous cell metaplasia in nasal and pulmonary airways, which is a key feature of clinical rhinitis and asthma. Therefore, our results with the allergic brown Norway rats are opposed to the enhanced allergic responses associated with γT, as described in vitro and in BALB/c mice (5, 6). The use of different rodent species (brown Norway rat vs. BALB/c mouse) may contribute to the disparate observations in these animal models. Furthermore, we provided γT by oral delivery rather than by the subcutaneous route in mice, which would bypass liver metabolism. This is an important distinction considering that the anti-inflammatory metabolites of γT are known to be more potent than those of its precursor in inhibiting COX-2- and 5-LOX-mediated eicosanoids (7, 8). Epidemiologic data suggesting positive correlations between plasma γT levels and diseases including lung disease are intriguing. However, there are many interpretations that can be made from these associations. One is, as the authors suggest, that γT promotes lung and inflammatory disease. A second is that these diseases result in an increase of γT as a response to ongoing disease. A third is that γT may be a co-nutrient with other agents that promote disease. Indeed, many plant oils that are commonly used in the United States but not Europe (such as corn oil and soybean oil) not only contain high levels γT but are also high in polyunsaturated fatty acids and n-6 fatty acids, which are known to contribute oxidative stress and promote inflammation. Thus, the apparent effect of γT may be a result of the polyunsaturated fatty acids and n-6 fatty acids contained in these oils. Interestingly, safflower and olive oils, which contain relatively high α-tocopherol levels and are commonly used in Europe, are rich in monounsaturated fatty acids, which are resistant to oxidative stress and inflammation. Although animal studies and epidemiological studies provide important data regarding the actions of both γ- and α-tocopherol in inflammatory processes, only intervention studies can demonstrate the actions of these variants of vitamin E on inflammatory processes in humans. We have published two oral intervention studies in humans using a γT-enriched preparation. In these studies, we have shown that active treatment is associated with decreased ex vivo response of peripheral blood monocytes to LPS, as well as airway inflammatory response to inhaled LPS (2, 9). We have also shown that peripheral blood basophils recovered from allergic volunteers have inhibited degranulation responses to allergen ex vivo (10, 11). These observations, coupled with our animal data, strongly support the hypothesis that γT has anti-inflammatory actions against both allergic and nonallergic inflammation. We do not disagree that α-tocopherol has anti-inflammatory actions as well, especially in light of the intervention studies cited by Cook-Mills and colleagues. Overall, we agree that nutritional and nutraceutical interventions represent exciting new and inexpensive approaches to decreasing allergic disease. We also agree that careful attention to dose, route of administration, duration of therapy, analyses of serum levels of tocopherols (and their metabolites), and clinical endpoints will be important in defining the role of tocopherols in asthma therapy. Thus, extending the investigation of the roles of α- and γ-tocopherol in the modulation of allergic and inflammatory disease into human populations is needed to fully understand the roles of these agents in allergic disease.