Free radicals participate in many diseases and states, e.g., inflammation, tumors, atherosclerosis, degenerative neurological diseases, etc.

Free radicals in the nasal cavity can be produced in many ways. Free radicals mostly come from white blood cells, which release them as part of the inflammatory response. Increased amounts of free radicals released by leucocytes during inflammation can kill bacterial, molds, yeasts, and parasites. Formation of free radicals is supported by cytokines IL-1 (interleukin-1) and TNF-α (tumor necrosis factor-α). Other sources of free radicals are reperfusion after ischemia and cell necrosis associated with the release of purines which are oxidized by xanthine oxidase to produce two superoxide radicals. Free-radical formation occurs in association with bleeding into tissues which releases iron that catalyzes the Fenton’s reaction and generates free hydroxyl radicals from hydrogen peroxide. In mucous tissue, free radicals can be formed by exposure to UV light. Mucous membranes lack melanin and therefore lack UV protection. Exogenous free radicals can come from air pollution, from foods, and from cigarette smoke. Hyperglycemia is also a source of free radicals via AGE-substances (advanced glycation end-products), which can destroy proteins and upregulate catalase other generators of free radicals. Formation of these free radicals can be blocked by amino-guanidine, lysine, nicotinamide, thiamine pyrophosphate, pyridoxamine, and certain antioxidants.

Free radicals can be created in association with reperfusion after ischemia, during ischemia via metabolism of purines released from DNA of damaged cells, catecholamines, prostaglandins, advanced glycation end-products, during biosyntheses of uric acid, in diabetes mellitus, during renal insufficiency, and from external sources like X-rays, harmful air pollutants, UV light, various drugs, tobacco smoke, psychological stress, pain, and many other factors. Each puff of a cigarette contains 100 trillion free radicals of varying types. Hypochlorous acid from hydrogen peroxide is formed as a result of the action of myeloperoxidase in nasal tissues. This acid harms tissues; however, in low concentrations hypochlorous acid (HOCl) has been shown to exhibit both antibacterial and anti-influenza virus activity. HOCl treatment can significantly inhibit human rhinovirus-induced secretion of IL-6 and IL-8 and significantly reduce viral titer (Yu et al. 2011). Some of the most common ROS are superoxides, free hydroxyl radicals, singlet oxygen (¹O₂), hydrogen peroxide, peroxynitrite (ONOO⁻), and nitric oxide (NO). Ozone directly increases the level of free radicals and DNA synthesis. Exposure to ozone impairs mucociliary transport by nasal epithelia, increases cell permeability and facilitates the influx of inflammatory cells with proliferative and secretory responses. Cytokines are released, as well as cyclooxygenases and lipoxygenases which increase free radicals and decrease mucociliary clearance.

Due to the number of free radicals and ROS involved in nose pathology, antioxidants are important to maintain normal function or correct dysfunction. There are many antioxidants produced by the body, or absorbed from food or even consumed directly as drugs or chemical compounds. Intracellular antioxidants include reduced glutathione and thioredoxin reductase, while extracellular antioxidants include uric acid, albumin, proteins, bilirubin, vitamin C, β-carotene, vitamin E, and folic acid. Enzymatic antioxidants include superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, while inorganic antioxidants include selenium, zinc, and magnesium. Antioxidant drugs include allopurinol, local anaesthetics, calcium channels blockers as well as many others. Quercetin and coenzyme Q₁₀ are locally acting antioxidants that can protect mucosal cells of the nasal turbinates which have previously been in contact with hydrogen peroxide (Reiter et al. 2009). Coenzyme Q₁₀ inhibits mitochondrial lipoperoxidation, supports ATP (sodium adenosine triphosphate) production and ROS removal. Therapeutic application of coenzyme Q₁₀ is limited it poor solubility and poor bioavailability (Fetoni et al. 2009). Physical training increases total antioxidant capacity, uric acid, SOD and GPx and decreases Complex Regional Pain Syndrom – Type – I. (Rahman et al. 2010; Gonzáles et al. 2008).

Unpaired electrons are needed to destroy free radicals. The earth has a limitless supply of free and mobile electrons. Molecular hydrogen (H₂) acts as an antioxidant and removes free hydroxyl radicals (^•OH), improves sleep, and decreases pain and inflammation. Molecular hydrogen has the ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.

Inflammation is a common feature of nasal and paranasal diseases. Inflammation can be caused by free radicals, which in turn attract leucocytes to the inflamed area, which then increase production and release of free radicals in an effort to fight inflammation. Inflammation, infection, and sepsis also attract increasing numbers of phagocytes, especially macrophages. Dead and dying leucocytes, in the form of pus, represent a source of free radicals that must be removed to avoid further free radical-induced damage. This is especially important in newborns, since their antioxidant defense system is immature and undeveloped. Inflammation triggers production of free radicals in phagocytes and target cells through TNFα. This initiates an inflammatory cascade in which free radicals act on macrophages further activating TNFα, and which in turn leads to the release of IL-1, IL-2, IL-6, IL-8, and IL-12. This cascade leads to an increase in hydrogen peroxide, the additional release of cytokines, and the formation of prostaglandin (PGE2), leukotrienes, and other inflammatory mediators. Activation of thrombocytes causes release of arachidonic acid from platelet cell membranes. Arachidonic acid is a precursor for prostaglandins, leukotrienes as well as the vasoconstrictive substance thromboxane A2. Compounds which protect the integrity of proteins are blocked by free radicals, which leads to an increase in elastase, collagenase, and other compounds that degrade proteins. Oxidative stress causes a decline in immunity. The free radical superoxide lowers the level of antibodies produced in response to immunization. Glycated proteins, AGEs and peptides are receptor agonists (RAGE—receptor of advanced glycation end-products) and lead to long-lasting inflammation, followed by chronic production of new free radicals. Inflammation and markers of inflammation can be reduced through the use of antioxidants. Antioxidants used to treat inflammation can improve immunity and diminish the actual inflammation itself. Antioxidant therapy is useful for treating oxidative stress, but the interrelationships between free radicals, cytokines, and activated lymphocytes are very complicated and it cannot be just assumed that oxidative stress causes immunodepression and antioxidant therapy leads to immunostimulation.

In chronic inflammation and uveitis, low serum levels of zinc and selenium are often found. The level of these trace elements tends to decrease with age, tending to make older individuals more susceptible to these inflammatory conditions.

Inappropriate expression of genes that maintain the sinonasal innate immune system very probably explains the pathogenesis of chronic rhinosinusitis with nasal polyps. Activated eosinophils may lead to the production of hypobromous acid (HOBr) and hypochlorous acid (HOCl), which are modified to 5-bromocytosine and 5-chlorocytosine. Then aberrant methylation of cytosine, during DNA replication, leads to an alteration in gene expression seen in patients with chronic rhinosinusitis with nasal polyps (Seiberling et al. 2012).

There are various relationships between bronchiectasis, chronic rhinosinusitis, and nasal polyposis. Most patients with bronchiectasis also have rhinosinusitis with rhinorrhea and nasal congestion. Patients with chronic rhinosinusitis have lower levels of NO before, as well as after, the operation. Patients with polyposis have significantly lower nasal NO levels (Guilemany et al. 2009). Olfactory function and nasal NO concentrations are correlated in chronic rhinosinusitis patients but not in healthy subjects. The production of nasal NO by paranasal sinuses does not seem to directly influence olfactory function (Elsherif et al. 2007). Exhaled NO appears to come mainly from the paranasal sinuses and nasal mucosa. Metabolites of NO and NO itself are significantly higher in the maxillary sinuses of patients with chronic sinusitis. Increased levels of NO and its metabolites in the sinuses are correlated with damage to the epithelia lining healthy sinuses (Naraghi et al. 2007). Olfactory function and nasal NO are both reduced in patients with chronic inflammatory sinonasal diseases, but without a clear explanation of its cause. Nasal NO production seems to decrease with age and is associated with overall olfactory function (Gupta et al. 2013).

Exhaled NO is produced by the respiratory mucous membranes of the nose and accessory nose cavities. Levels of NO metabolites are significantly higher in the maxillary sinuses, especially in patients with chronic sinusitis. The impaired epithelia lining of the sinuses play an important part in the pathogenesis of sinusitis (Naraghi et al. 2007). In acute maxillary sinusitis, increased lipoperoxidation (increased malondialdehyde) and SOD are seen in the mucosa. In chronic sinusitis there are decreased levels of serum IL-12, alpha-tocopherol, uric acid, and SOD found in the tissues.

The lower the levels of GSH (reduced glutathione), uric acid and SOD, the more severe the disease appears to be. Antioxidant supplementation may be helpful. Biopsies of the nasal mucosa have shown decreased level of GSH, uric acid, and decreased antioxidant capacity in patients with chronic sinusitis. There were no significant differences with regard to vitamin E and GSSG (oxidized glutathione) levels relative to controls. GSH is consumed as it removes free radicals; a decrease in uric acid levels can be explained by the protection from oxidation by vitamin C and the binding of transition metals. This reaction irreversibly degraded uric acid, which is not synthesized in the nose, but is absorbed there from blood. The air along with NO is humidified during passage through the nasal sinuses. This increases the power of the airways to defend against radicals (Akatov et al. 2000; Westerveld et al. 1997).

Nitric oxide is a diffusible, transient, reactive molecule that has physiological effects in the picomolar-to-micromolar range. Acting through soluble guanylate cyclase activation, NO is an important physiological regulator of the cardiovascular, nervous, and immunological systems. NO is bioavailable through two routes. It can be endogenously generated by constitutive or induced enzymes like nitric oxide synthase. The formation of NO from l-arginine represents an alternative pathway for nitric oxide generation. Nitrates and nitrites can be reduced to nitric oxide and other bioactive nitrogen oxide species, especially during hypoxia and acidosis. Orally ingested nitrates/nitrites are rapidly taken up into the circulation and subsequently converted to NO-species. This contributes to the defense of the tissues, regulation of blood flow, cell metabolism, and NO signaling. NO has multiple effects on tissues. NO plays an important role in vasodilatation, bacterial aggression, cytokine stimulation, regulation of mineralized tissue function, neurotransmission, platelet aggregation, etc. However, under pathological conditions, it can be quite damaging as in periodontal disease and oral cancer (Udgar-Cankal and Ozmeric 2006; Weitzberg et al. 2010). Chewing supports its production and increased perfusion accelerates healing. Nitric acid and saliva radical have significant antibacterial effects. The same antimicrobial effect has saliva (Rettori et al. 2000). Smokers have lower levels of NO than nonsmokers (Hays et al. 1992; Seri et al. 1999). Decreased serum levels of NO and increased levels oxLDL (oxidized low density lipoproteins) are also seen in patients with obstructive sleep apnea-hypopnea syndrome. This can promote the formation of atherosclerosis. There is a correlation between endothelial dysfunction and the severity of hypoxia (Jiang et al. 2011; Marteus et al. 2005).

Cigarette smoking reduces the level of nitric oxide in exhaled air. This reduction occurs mainly in the oropharynx. Smokers exhaled 67 % lower levels of NO than controls. There were no significant differences in salivary nitrite, nitrate or ascorbate between smokers and nonsmokers. Cigarette smoking does not affect nonenzymatic NO formation from nitrite in saliva, but decreases enzymatically produced NO (Marteus et al. 2005). Mouthwash with antibacterial chlorhexidine reduced salivary nitrite by 65 % and exhaled NO levels by 10 %.

The nitric oxide radical (NO) is very important in these diseases. NO is a fundamental signal molecule associated with wound healing. It is an important cofactor with regard to the migration and proliferation of keratocytes as they relate to angiogenesis and collagen deposition. The level of NO in the nose is affected by age, physical load, smoking, and a variety of drugs. Vasoconstrictive drugs decrease the level of NO in the nose, but the reduction can be due to a mechanism other than vasoconstriction. Vasoconstriction of mucous membranes in nose is affected by the physical load, but NO is not reduced under this condition (Serrano et al. 2007). Neuropeptide Y reduces the passage of blood through the nasal mucous membranes. Obstruction of air flow through the nose is influenced by thromboxane A₂ which causes congestion and leukotriene D₄ which likely produces vessel dilatation in the nasal mucosa. Pathological levels of NO are primarily associated with ciliary dyskinesis, allergic coryza, sinusitis, nasal polyposis, and cystic fibrosis. NO functions are mainly protective i.e., antimicrobial and antiviral. Antibiotics in sinusitis will not prevent free radical impairment in the tissues. Addition of vitamin A to the antibiotic treatment regime decreases lipoperoxidation and reduces the extent of histopathology (Guven et al. 2007). However, SOD activity was found to be higher when antibiotic therapy was used alone. Bioparox spray inhibits the synthesis of free radicals and the effects of IL-1 and TNF-α; while at the same time it potentiates the anti-inflammatory effects of IL-2 and INF-γ (interferon-γ).