**2.2. Oxidative stress in influenza virus infection**

mortality are greatest in infants, the elderly, and those with underlying illnesses—chronic pulmonary or cardiovascular diseases, and diabetes mellitus. The severe complications include hemorrhagic bronchitis or pneumonia (primary viral or secondary bacterial). In addition, fulminant fatal influenza viral pneumonia can occur, with death proceeding in as little as 48 hours after the initial flu symptoms [1]. The World Health Organization recommends influenza vaccines as a main tool for preventing infection and anti-influenza chemotherapeutics with antiviral drugs for treatment and/or prophylactically [1]. The antivirals effective against influenza are divided into two types based on their modes of action: (i) inhibitors of the neuraminidase—oseltamivir, zanamivir, peramivir, and related compounds, efficacious against influenza A and B virus infections, and (ii) blockers of the protein M2—rimantadine-HCl and amantadine-HCl, active against influenza virus A infections. Although both types of agents have proven antiviral effectivity, the rate of drug resistance is constantly increasing,

Two principal problems are related with vaccine prevention: (i) anti-influenza vaccines commonly demonstrate 70–90% effectivity in young persons, with rates markedly decreasing in the elderly; (ii) the protection length is limited to a few months or a season because of the continuous viral antigenic drift based on gradually accumulated mutations, requiring annual

The pathogenesis of influenza virus infection is associated with two general processes in the human body: (i) local lung damage due to viral replication in the columnar ciliary epithelium of bronchi and bronchioles, which leads to progressive damage of the alveolar cells, bronchopneumonia (viral or combined viral-bacterial), massive bronchitis (including bronchiolitis), and the like, as the major causes of death [4]; (ii) a dramatic inflammatory burst that induces among other processes an increase in reactive oxygen species generation, causing extensive damage in cellular membranes, predominantly in the small vessels, arterioles, and capillaries [5–8]. In addition, extrapulmonary complications affect many organs and tissues, such as heart, brain, middle ear, liver, and endocrines, and even stomach and kidneys, though that is

Influenza virus replicates in the respiratory tracts of humans, mainly in the lungs. Extrapulmonary multiplication of this virus has not been proven in people with influenza, nor in experimental conditions in influenza virus-infected laboratory animals. Influenza virus replicates throughout the whole respiratory tree. Tracheobronchitis is the common clinical picture of influenza. In the acute stage, multifocal destruction and desquamation of the columnar epithelium of the trachea and bronchi accompanied with edema and congestion of the submucosa are characteristic. In about 50% of cases, tracheitis and bronchitis have a hemorrhagic character. Cell necrosis is the final stage of desquamation of the affected epithelium

especially for M2 blockers [2].

68 Vitamin E in Health and Disease

**2. Influenza pathogenesis**

**2.1. Respiratory tract damages**

revaccination [3].

rare [9–14].

Lungs are the target organs of the influenza virus. However, in the course of influenza virus infection, dynamic changes in oxidative metabolism, provoked by the overgeneration of ROS (reactive oxygen species) and the activation of neutrophils, can reach the development of oxidative stress [5, 18, 19, 22–24]. Oxidative stress is defined as a disturbance of the prooxidant-antioxidant balance in favor of prooxidants. Influenza viruses are known to induce ROS-generating enzymes and to disturb antioxidant defenses [5, 18, 19, 25], causing changes in antioxidant enzyme activity [5] and decreases in endogenous low-molecular-weight antioxidants. Overgeneration of ROS may influence signaling pathways by activating "redox switches" [26]. In lungs, redox homeostasis is crucial in the pathology of influenza because it is associated with cytokine production, inflammation, cell death, and other pathological processes that could be triggered by enhanced ROS generation (**Figure 1**).

Since the products of oxidative stress possess high cytotoxic activity, it is very important to study mechanisms of detoxification in the infected body. After the epithelial cells are infected, tissue-resident alveolar macrophages are the first responders to viral infection in the lungs (**Figure 1**). They can promote viral clearance through the phagocytosis of viral particles or infected apoptotic cells (efferocytosis) and the release of a plethora of inflammatory cytokines and chemokines to initiate and drive the immune response [27–30] . Due to the ability of ROS to react with almost any kind of biological molecule, including proteins, lipids, and nucleic acids, their elevation is generally associated with genome instability, dysfunction of organelles, and apoptosis [31].

Antioxidant defense mechanisms, including enzymes like superoxide dismutase, catalase, and small molecules such as vitamins C and E and glutathione, protect tissues against oxidants [32].

**3. Vitamin E and influenza virus infection**

organism's antioxidant protection diminished [18, 19, 22, 23, 25].

peroxidation products.

animals [19, 44–47].

Values are expressed as means ± SEM [41].

infected with influenza virus A/Aichi/2/68 H3N2 (1.5 MLD50).

damage.

It has been proven that oxidative stress in the influenza virus-infected organism provokes free-radical oxidation of unsaturated lipid chains in the cell membranes (lipid peroxidation), which reduces their permeability as a whole. In the presence of antioxidant deficiency, as described below, when all cell membranes are exposed and/or damaged, influenza infection proceeds with severe pathology and results in serious damage at all levels in the body [38].

Vitamin E and Influenza Virus Infection http://dx.doi.org/10.5772/intechopen.80954 71

It was established that, during influenza infection in mice, the activity of antioxidant enzymes SOD and catalase were changed, along with a decrease of the amounts of endogenous lowmolecular-weight antioxidants such as α-tocopherol (**Table 1**), glutathione, and ascorbate [19, 24, 39–41],). Endogenic levels of vitamin E were significantly decreased in lung, liver, and blood plasma [19, 23, 42]. In addition, changes in cytochromes were recorded as well as decreases in the activities of liver cytochrome P-450-dependent monooxygenases [18, 43]. Together, these facts indicate that, in the course of the disease, the buffering capacity of the

These data demonstrate that, during influenza virus infection, a decrease in natural antioxidant vitamin E was established, accompanied by a significant increase in endogenous lipid

Oxidative damage in the course of influenza virus infection is quite large, even when registered in experimental animals (mice) at low virus-inoculation doses. In conditions involving non-infected animals with suppressed antioxidant defense systems, the consequent inoculation of influenza virus resulted in an acceleration of oxidative stress and graduated tissue

Different conditions can favor the host's susceptibility to influenza virus infection; among them are cold exposure and stressors of physical, chemical, and psychological origin. For example, immobilization and cold-restraint stress are widely used experimental models that are accompanied by a considerable decrease in the antioxidative capacity of the animal organism; they are also used for the indirect modulation of antioxidant deficiency in experimental

Because of the significant role of oxidative stress in the pathogenesis of influenza virus infection, a lot of work has been done to test the influence of antioxidants on the course of influenza. Drugs stimulating NRF2 pathway are tested for treatment of diseases causing oxidative

**5th day 7th day 5th day 7th day 5th day 7th day**

**Table 1.** Endogenous content of vitamin E [nmol/mg protein] in lung, liver, and blood plasma of mice experimentally

I Control 2.2 ± 0.31 2.14 ± 0.26 4.94 ± 0.51 5.4 ± 0.42 1.8 ± 0.065 1.72 ± 0.07 II Flu 1.47 ± 0.14 1.7 ± 0.17 3.35 ± 0.42 3.12 ± 0.37 1.46 ± 0.035 1.2 ± 0.37

**Group Lung Liver Blood plasma**

**Figure 1.** Respiratory tract damages, causes by influenza virus infection.

Vitamin E is the most active natural fat-soluble antioxidant capable of protecting unsaturated fatty acids in cellular membranes from peroxidation, thereby contributing to membrane stability [33]. Both human clinical trials and animal studies have shown a beneficial effect of supplemental vitamin E on the immune system [34].

Studies in the last decade established that the nuclear factor (erythroid-derived 2)-like 2 (NRF2) encoded in humans by the NSF2 gene, is a protein regulating the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. NRF2 controls the basal and induced expression of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. NRF2 has a substantial impact on oxidative stress and toxicity, regulating the antioxidant defense [35].

At this point of view, the oxidative stress is caused by the imbalance between production of reactive oxygen species (ROS) and the body's ability to detoxify the reactive intermediates.

Recent studies described the role of NRF2 gene coded protein in the development of oxidative stress. The antioxidant pathway controlled by NRF2 is pivotal for protection of lungs against the development of influenza virus infection-induced pulmonary inflammation and injury under oxidative conditions. The NRF2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation induced by influenza virus infection [36, 37].
