**4. Effects of vitamin E supplementation**

stress, influenza virus infection included [48]. Experiments on in vivo models, predominantly

Among the antioxidants tested against influenza virus infections in mice [17, 49–52] α-tocopherol (vitamin E) occupies the leading position. This is because of its efficacy in preventing oxidative damage through its free-radical scavenging activity [16, 18, 24, 42, 53–55]. Protein expression of NRF2 is found to be increased in both the cholesterol-fed and the vitamin E-supplemented rabbits via activation of NRF2 pathway, resulting in induction of several antioxidant genes. Vitamin E appeared to afford the protection effect of NRF2 [48, 55]. Besides, it was found that vitamin E prevents the NRF2 suppression by allergens in alveolar

These data clearly show the role of antioxidants, such as vitamin E, which can be manifested in several ways: (i) to capture free radicals in enzymatic or non-enzymatic mechanism(s), (ii) to suppress their generation, and (iii) to affect these processes in an indirect way, for example,

As vitamin E is a lipid-soluble substance and possesses a hydrophobic tail, it tends to accumulate within the interior of lipid membranes. There, it acts as the most important chain-breaker, as it reacts with lipid peroxyl radicals about four times faster than they can react with adjacent fatty acid side chains. It is well known that vitamin E is able to prevent oxidative damage [58–61], because its lipophilic structure contributes to easy and passive diffusion through the cell membranes, allowing it to reach the mitochondria and the single-plated reticulum. In this way, vitamin E protects them against lipid peroxidation and damage (**Figure 2**). Especially important is its termination of free-radical chain reaction, which protects membrane polyun-

Vitamin E is known to affect inflammatory responses in different tissues, including the lung, not only via direct quenching of oxidative stress [42, 62], but also through modulation of oxidative eicosanoid pathways and prostaglandin synthesis [58, 63, 64], inhibition of inflammatory mediators [59], and control of apoptotic lipid signaling [60]. A stabilizing role of Vitamin E

**Figure 2.** "Bermuda triangle" composed by the pathogenesis of influenza virus infection in the infected body. Vitamin

saturated fatty acids from oxidation involving reactive oxygen species [61].

has a stabilizing role for membrane phospholipids [61] (**Figure 2**).

in mice, hold a significant place in such investigations.

macrophages, proved for asthmatic model in vivo [56, 57].

by inhibiting viral replication.

72 Vitamin E in Health and Disease

E action is directed to the storm center.

As mentioned above, investigations on mice experimentally infected with influenza virus found that endogenous vitamin E content was significantly decreased after influenza virus inoculation. In addition, the amount of cytochrome P-450 in the liver and the activity of cytochrome *c* reductase decreased by about two times on the 5th–7th days post virus inoculation. The decrease in cytochrome P-450 was found to correlate with increases in the concentration of lipid peroxidation products in liver, lung, and blood [18]. Influenza virus infection significantly inhibits liver monooxygenase activity. As a consequence, products from the decreased enzymatic function accumulate in the liver, resulting in the destruction of cytochrome P-450 and its transformation to the catalytically inactive P-420 form.

The effects of influenza virus infection on liver monooxygenases and lipid peroxidation are different from the effects of the hydrophobic xenobiotic substrates of cytochrome P-450. Evidently, the oxidative stress induced in the liver by hydrophobic xenobiotics is a consequence of enhanced oxidation by cytochrome P-450-dependent monooxygenases. The decrease in liver monooxygenase activity resulting from influenza virus infection is accompanied by increases in lipid peroxidation products in the liver, which is not a result of activation of cytochrome P-450-dependent monooxygenases. It may be presumed that influenza virus induces free-radical processes outside the liver, thus producing free radicals and/or activated oxygen species. These reactive compounds must diffuse or be transported over the hepatocyte barrier to initiate lipid peroxidation in the liver.

The protective effect of vitamin E against lipid peroxidation was dose-dependent and was more pronounced on the 5th day as compared to the 7th day after virus inoculation [18, 22]. This agrees with data from Peterhans [5] and Jacoby and Choi [38]. Vitamin E supplementation led to stabilization of cytochrome P-450. Concentrations of the hepatic cytochrome P-450 in infected mice reached the values found in control (non-infected animals) after vitamin E supplementation (120 or 240 mg/kg b.w.), because the monooxygenase activities were restored.

However, researchers have shown that endogenic levels of vitamin E are significantly decreased in lung, liver, and blood plasma (**Table 1**) during the course of flu infection [21, 23, 24, 42]. Animal and human studies have demonstrated a negative correlation between endogenous levels of vitamin E in the body and pulmonary inflammations, and exogenous vitamin E supplementation has been tied to reducing severe symptoms of lung disease [16, 18, 64].

had the strongest effect. The superior protective effect of the combination is probably due to the better interaction between hydrophobic and hydrophilic low-molecular-weight antioxidants against a free-radical disease like influenza. The mechanism of this interaction is related to vitamin C's ability (when situated in aqueous phase) to recycle vitamin E (located in membranes), repairing vitamin E's tocopheroxyl radical. Thus, vitamin C promotes the

Vitamin E and Influenza Virus Infection http://dx.doi.org/10.5772/intechopen.80954 75

An underappreciated approach in flu therapy continues to be combination administration regimens of specific viral replication inhibitors together with antioxidants. Therefore, investigations on the combination effects of specific anti-influenza chemotherapeutic agents and antioxidants are of special interest. Previously, we established a favorable combination effect of the antioxidant 4-methyl-2,6-ditretbutylphenol (ionol) with M2-blocker rimantadine in mice infected with influenza virus A(H3N2). Ionol was administered intraperitoneally in a 3-day course (45 or 75 mg/kg daily) before virus inoculation, and rimantadine (oral applica-

Recently, a strong beneficial effect of the combination of α-tocopherol (a component of vitamin E) and oseltamivir was demonstrated in the treatment of experimental infection with influenza virus A/H3N2 in mice [76]. The results showed that this combination of agents simultaneously suppressed the two main processes in the pathogenesis of influenza—the development of pulmonary lesions in the respiratory tract as a result of virus replication and the oxidative stress damage to membranes of small vessels and other tissues in the body—

However, a question arose: Is oseltamivir an antioxidant? We used some model systems to test oseltamivir's ability to scavenge superoxide radicals, to inhibit their generation, and to influence Fe2+ or (Fe2+-EDTA)-induced lipid peroxidation in liposomal egg suspension and in lung and liver microsomes [77]. We concluded that the reduction of oxidative stress in vivo is not connected with oseltamivir's effect on the development of free-radical processes in the organism. Oseltamivir's effect on oxidative stress in the course of viral infection could be explained by its specific therapeutic effect, which is connected with suppression of viral rep-

The in vivo antiviral activity of the combination vitamin E + oseltamivir, expressed by a marked protective effect on the survival of influenza A virus-infected animals, was recorded when vitamin E was administered simultaneously with oseltamivir phosphate via a 5-day course post virus inoculation [76]. This effect was not observed when the vitamin E course started 120 or 48 hours before viral inoculation. According to this study, vitamin E applied individually had no effect on the course of influenza A virus infection caused by 10 MLD50. Only a lower value of the lung index was registered. In our previous study, we established a

Special attention should be paid to the sharp synergistic character of the antiviral effect of the combination vitamin E and oseltamivir at a dose of 0.625 mg/kg administered simultaneously, which resulted in the following: (i) a pronounced increase in the protection index, attaining 76%, and a lengthening of the MSD by 3.2 and 4 days; (ii) a pronounced decrease in

tion of 15 mg/kg) was administered for 5 days following the day of infection [75].

function of vitamin E as a free-radical scavenger [73, 74].

thus characterizing it as a very good prospect for flu therapy.

protective effect of vitamin E at virus infection with 2 MLD50 [18, 24].

lication in the target organ.

It is well known that vitamin E is able to prevent oxidative damages [58–60].
