Oxidative Stress and Low Glutathione in Common Ear, Nose, and Throat Conditions:
A Systematic Review
Benjamin F. Asher, MD, FACS; Frederick T. Guilford, MD
ABSTRACT
Context • Oxidative stress and tissue-damaging, oxygen (O2)-related, free-radical formation is inherent in human metabolism, and the tissues of the ear, nose, and throat (ENT) have an increased exposure to injury from those substances. Because glutathione (GSH) is a major component in an antioxidant defense against oxidative damage in ENT tissues, a review of the impact of lowered GSH and oxidative stress in conditions associated with the upper respiratory tract is warranted.
Objective • The review intended to summarize the role that oxidative stress and GSH play.
Design • The research team performed a literature review from 1980 to the present that was based on the following keywords: oxidative stress, oxidation, antioxidant, and GSH in common ENT conditions. The review found the following conditions: (1) rhinitis, (2) allergic rhinitis,
(3) chronic rhinosinusitis (CRS), (4) CRS with polyps, (5) otitis media with effusion, (6) chronic otitis media (COM), (7) COM and cholesteatoma, (8) tympanic membrane sclerosis, (9) tonsillitis, (10) Meniere’s disease, (11) laryngeal conditions, and (12) chronic cough.
Results • ENT conditions have been found to be associated with oxidative stress and with low GSH. A limited number of the reviewed studies discussed antioxidant use or repletion of GSH. Although only a few reports support the use of GSH or antioxidants as adjuncts in the management of ENT conditions, no reports of side effects were found related to their use.
Conclusions • Many ENT conditions are associated with oxidative stress and decreased GSH, both locally in the affected tissues and systemically. The oxidative stress of those conditions may be related to depletion of GSH, which is increased by the higher levels of O2 in the upper respiratory tract. A small number of studies have reported clinical benefits from the use of an antioxidant or GSH support. The findings of benefits and the lack of reports of side effects suggest that the clinical use of antioxidants and support with GSH in ENT conditions may be considered as adjuncts to conventional management and that more research is warranted. (Altern Ther Health Med. 2016;22(5):44-50.)
Benjamin F. Asher, MD, FACS, is a clinician at Asher Integrative Ear, Nose and Throat in New York, New York. Frederick T. Guilford, MD, is a clinician and science officer at Your Energy Systems, LLC, in Palo Alto, California.
Corresponding author: Frederick T. Guilford, MD
E-mail address: drg@readisorb.com
Oxygen (O2), necessary for the production of energy in the mitochondria of human cells, also contributes potentially damaging O2 components known as oxidizing free radicals, a situation that has been termed the oxygen paradox.1 In humans, ambient levels of O2 of approximately 21% are needed for normal body function, but increased levels of O2 exposure stimulate oxidative lung injury due to the formation of free O2 radicals, such as superoxide (O2−), the hydroxyl radical (•OH), and singlet oxygen (1O2), which lead to oxidative stress.2
Antioxidants are critical in the defense against oxidative stress, and it has been shown that glutathione (GSH) and glutathione peroxidase (GPx), a selenoenzyme, play a significant role in that defense.3 A major function of GSH is the protection of cells against O2 toxicity.4 In the lung, the concentration of GSH in the epithelial lining fluid (ELF) of the alveolar surface is 140-fold higher than that of the plasma of the same individual, and 96% of the GSH in the ELF is in the reduced form.5
Although the air encountered in the ambient environment contains 20% O2, the concentration circulating to cells in tissues at physiologic concentrations is approximately 5%. Reactive oxygen species (ROS) increase in the airway during the inhalation of 100% O2, and they participate in the development of pathology,6 which usually occurs within 12 hours of exposure to 100% O2 in human volunteers.7
Found in body tissues, macrophage cells that have been grown at 20% O2 have shown more ROS, lower reduced GSH, and increased production of inflammatory mediators than have cells grown at the physiologic concentration of 5% O2 that is found in tissues.8 The incessant oxidizing challenge in the mucosa of the upper airway requires those tissues to have a constant antioxidant defense.
The wide range of O2 tension occurring in sinuses can lead to oxidative stress in the upper airway. A partial pressure of oxygen (pO2) of 96 mm HG (ie, the normal level in arterial blood) has been shown to be present in nonpurulent secretions of the sinuses, whereas purulent secretions have shown almost no pO2.9,10 Ischemia, with its accompanying lack of O2, has been shown to lead to decreased GSH.11 Thus, too much or too little O2 can become an oxidizing problem. Because GSH is a major component in an antioxidant defense, a review of the effect of lowered GSH and oxidative stress in conditions associated with the upper respiratory tract is warranted.
The upper respiratory tract functions to protect the lower respiratory system from biological and chemical agents in the inspired air. Those exposures often result in oxidative responses related to ROS, which have been well described with regard to oxidant environmental pollutants, ozone and nitrogen dioxide, ambient particulate matter, and cigarette smoke.12-15
Upregulation of the antioxidant system generally protects the airway and lungs against ROS, but an increased amount of oxidant-producing material can overwhelm the system. The role of oxidants in the pathogenesis of asthma is notable because the pathophysiological characteristics of asthma and of chronic infections of the upper airway tract are related.1
GSH is a critical component in both the intracellular and extracellular defense systems of the airways.17,18 Cells exposed to ambient concentrations have increased GSH levels because human alveolar epithelial cells of the lungs have basal GSH levels of 150 nmol/mg protein compared with 10 nmol GSH/mg protein in human, peripheral, mononuclear cells in the blood.19 Extracellular glutathione peroxidase (eGPx) in the lungs is a major antioxidant in the epithelial lining fluid and couples with GSH or S-nitrosoglutathione to detoxify lipid peroxides.6
The level of GSH in the nose has been found to be lower than the level in the lungs. However, the level in nasal mucosa appears to be important because irritants such as naphthalene or acrolein can result in a depletion of mucosal GSH,20 and decreased GSH levels have been found in the mucosa of individuals with chronic rhinosinusitis (CRS) as compared with the mucosa of normal individuals. A GSH wet weight of 0.6 μmol/g has been found in normal controls, whereas patients with CRS had GSH levels of 0.3-μmol/g wet weight in the mucosa.21 Glutathione disulfide (GSSG), which is oxidized GSH, is generally maintained at one-tenth the level of reduced GSH.21 Although the levels of GSH differ between the nasal mucosa and lung’s alveolar mucosa, GSH is important at both ends of the respiratory system.
The current review has been prompted by the recent publication of a clinical study describing the use of oral liposomal GSH in relieving oxidant stress in the immune cells and in supporting the immune defense in individuals with human immunodeficiency virus (HIV), which is associated with chronic GSH deficiency.22
Role of GSH
Oxidation is the chemical process by which an atom, molecule, or ion robs another of 1 or more of its electrons. Chemicals that have a tendency to steal electrons are referred to as oxidizing agents or oxidants. The concept of oxidation is named after O2, the common oxidizing agent.
A free radical is defined as any chemical species containing 1 or more unpaired electrons.23 Oxidative stress occurs when an increase occurs in the production of free radicals and reactive metabolites (ie, oxidants) to levels that the cells are unable to eliminate by protective mechanisms (ie, antioxidants). Because free-radical molecules are highly reactive, they can cause cell and tissue damage, especially in cellular membranes, by reacting with cellular lipids, proteins, nucleotides, and carbohydrates.24
The ROS can initiate a radical chain reaction that can cause rapid spread and amplification of oxidative injury in biological systems.25 The excess of oxidants leads to damage of the biomolecules of cells, tissues, and organs, resulting in a harmful effect on the whole organism. The constant interaction between oxidants and antioxidants is part of the normal function of cells and can lead to differences in GSH concentrations within cellular and tissue compartments.18
Although GSH is central to the detoxification of ROS, it works most efficiently with an enzyme system that includes: GSH peroxidase, GSH S-transferase, and GSH S-conjugate efflux pumps.26 The pathways of GSH production have recently been reviewed.27,28
An important GSH, eGPx is synthesized by airway epithelium and alveolar macrophages and secreted into the surfaces’ epithelial lining fluid. It functions as a first-line defense against inhaled ROS.6
Ear, Nose, and Throat Diseases
The nasal mucosa is constantly bombarded by pathogenic and nonpathogenic particles and is protected by a multilayered defense system that includes mechanical, innate, and adaptive systems, each of which work together in a defense against inflammation and infection of the upper respiratory system.29 The first layer of mucosal defense includes a layer of glycoproteins and lysosomal contents, which make up a physiologic barrier of nonimmunologic molecules against invading debris.29
Material that bypasses the initial barrier is likely to be removed by the innate and adaptive—nonspecific and specific—immunological defense mechanisms. The innate or nonspecific immune response includes phagocytic cells such as macrophages, dendritic cells, and neutrophils and the complement system. The role of GSH in preserving the bacterial defense of innate immune cells has been described previously.22,27,30,31 The antibacterial activity of neutrophils results in the release of myeloperoxidase (MPO). However, the antibacterial activities of neutrophils can also result in the oxidative tissue damage found in many diseases.32 In addition, increases in nitric oxide (NO), which has both antioxidative and pro-oxidative properties, have been reported in inflammatory diseases.33
In contrast to the nonspecific or innate immune responses in the nasal mucosa, the specific or adaptive immunological defenses include cells that secrete antibodies specific to the antibody-generating (antigen) material, including secretory immunoglobulin (Ig) A, IgG, IgE, and immune-reactive cells in the nasal mucosa. Activation of either system can lead to inflammation.
The adaptive immune response is classically associated with inflammatory responses, including allergic responses. ROS and reactive nitrogen species (RNS), such as superoxide, hydrogen peroxide, NO, and peroxynitrite that are generated during inflammation, can cause additional stress by directly or indirectly breaking covalent bonds in DNA, proteins, and lipids.34 Note that several molecular mechanisms exist by which ROS and RNS can damage DNA, proteins, and lipids.
To achieve airway defense without airway inflammation or congestion, a balanced response to inhaled debris is needed from each layer of the defense: the mechanical, innate, and adaptive systems. Lack of balance or failure of those defenses leads to inflammation and infection of the upper respiratory system.29
Increased markers of inflammation and lipid oxidation—such as malondialdehyde (MDA), one of the most frequently used indicators of lipid peroxidation35—are generally associated with decreased GSH in cells.36 Additional markers of oxidative stress include 4-hydroxy-2-nonenal (4-HNE), which is formed from lipid peroxidation of omega-6 polyunsaturated fatty acids and also is associated with decreased cellular GSH.37
Oxidative stress has been shown to be a causal factor in a number of disease conditions such as atherosclerosis, carcinogenesis, rheumatoid arthritis, and several pulmonary disorders.38 Many acute and chronic inflammatory diseases of the airways are also associated with oxidative stress and include chronic obstructive pulmonary disease, asthma, chronic sinusitis, viral and bacterial infections, and idiopathic pulmonary fibrosis.21,39-44
METHODS
The research team performed a literature review from 1980 to the present that was based on the following keywords: oxidative stress; oxidation; antioxidant; and GSH in common ear, nose, and throat (ENT) conditions. The review found the following conditions: (1) rhinitis, (2) allergic rhinitis (AR), (3) CRS, (4) CRS with polyps, (5) otitis media with effusion (OME), (6) chronic otitis media (COM), (7) COM and cholesteatoma, (8) tympanic membrane sclerosis,
(9) tonsillitis, (10) Meniere’s disease, (11) laryngeal conditions, and (12) chronic cough.
RESULTS
The current review found that ENT conditions have been associated with oxidative stress and with low GSH. A limited number of the reviewed studies discussed antioxidant use or repletion of GSH. Although only a few reports support the use of GSH or antioxidants as adjuncts in the management of ENT conditions, no reports of side effects were found related to their use.
Rhinitis
Rhinitis is defined by the presence of 1 or more symptoms, including nasal congestion, rhinorrhea, nasal itching, and nasal obstruction.45 The 2 major classifications of rhinitis are allergic and nonallergic rhinitis (NAR).45,46
NAR has been defined as an inflammation in the nose that is not IgE-mediated.47 AR is characterized by rhinorrhea, congestion due to nasal obstruction, sneezing, and itching, and its symptoms are caused by an immunological mechanism after exposure to an allergen. AR is deeply related to other atopic diseases such as asthma. It is now generally recognized that most people with asthma have rhinitis.48
Allergic Rhinitis
AR is considered to be a nasal inflammation that is mediated by Th2 cytokines and is accompanied by an accumulation of eosinophils and mast cells in the nasal mucosa and increased serum levels of antigen-specific IgE.49,50
Even though it is well known that oxidant stress plays an important role in the pathogenesis of asthma, less is known about allergic rhinitis.51 It has been shown that generation of ROS to a degree that overwhelms the antioxidant defenses is critical for the amplification of inflammation in allergic diseases.52
Children with both AR and asthma have a marker of oxidative stress, MDA, in their exhaled breath condensates.51 In AR related to pollen, it has been shown that the pollens contain the activity of endogenous nicotinamide adenine dinucleotide phosphate (NADPH) oxidase,53 which functions to produce ROS and generates local danger signals in the epithelium of nearby airways. Those signals in turn trigger the early recruitment of granulocytes, even in the absence of the adaptive immune response.53
Pollen particles are known to contain antigens that stimulate an inflammatory response, including the formation of IgE-specific to the antigen.54 It has been proposed that pollen exposure induces a 2-signal mechanism that initiates allergic inflammation. The model consists of ROS that is generated by pollen NADPH oxidase, inducing oxidative stress (signal 1) that is independent of the adaptive immune response. Products generated by oxidative stress such as GSSG and 4-HNE facilitate the immunologically specific, allergic inflammation of airways that is induced by a specific pollen antigen (signal 2).55
A concept has been proposed that involves supplying antioxidant support to diminish the effects of the NADPH-oxidase-related component of the airway’s allergic inflammation, but no clinical study has been reported.56
Chronic Rhinosinusitis
CRS is a broad clinical syndrome that is characterized by prolonged mucosal inflammation of the nose and paranasal sinuses and is typically divided into 2 subtypes based on the presence or absence of nasal polyps.57 In a 1997 study, mucosa from the noses of individuals with chronic sinusitis was compared with that of healthy controls and showed a significant decrease in reduced GSH levels (P < .05) and uric acid.21 A 2002 article reported a significant negative correlation between GSH levels in sinus tissue and the severity of chronic sinus disease (P < .05).58
CRS With Polyps
The etiology of nasal polyps remains elusive, although inflammation and oxidative stress are considered major factors.59 It has been shown that free-radical damage occurs in nasal polyp tissue, with reports of high levels of MDA being indicative of oxidative stress in polyp tissue.60-63
Several articles have demonstrated that oxidative stress in both nasal polyp tissue and systemic blood59,64,65 corresponds to a diminished blood GSH in the patient group with nasal polyps,64 suggesting a systemic effect for oxidative stress that is associated with nasal polyp tissue.
It has been shown that adding a combination of antioxidants—vitamins A, C, and E—to steroid therapy for nasal polyps resulted in decreased tissue and serum levels of MDA.66
Otitis Media With Effusion
Chronic OME is defined as the presence of fluid in the middle ear (ME) without signs or symptoms of acute ear infection.67 It is a common pathologic condition characterized by nonpurulent fluid in the ME that leads to a moderate conductive hearing loss and a flat tympanogram.68
Microorganisms and endotoxin have been shown to be present in the fluid of individuals with chronic ME fluid, suggesting a bacterial contribution in OME.69,70 In one study, inflammatory cells generated large amounts of superoxide radicals to improve bactericidal activity, yet they also may have caused damage to the epithelium of the ME and to the ME fluid, samples of which were obtained during a myringotomy of children with OME who showed high levels of lipid peroxide.68
Studies of the systemic antioxidant status of children with OME have shown that children requiring tube insertion through adenoidectomy and myringotomy have significantly increased erythrocyte levels of MDA, an end product of lipid peroxidation, compared with healthy controls.71
Treatment of OME with nasal aerosol administration of reduced GSH in a controlled study suggested improvement in two-thirds of the patients with otitis media.72
Chronic Otitis Media
Chronic otitis media (COM) is defined as an inflammation of the mucosal linings of the air spaces of the ME and temporal bone, accompanied by perforation of the tympanic membrane, with a duration of more than 3 months. It has been shown that the MDA levels in the ME fluid of patients with COM is significantly higher than the MDA levels found in the effusion fluid of patients with OME.73
Serum MPO activity and the levels of MDA, 4-HNE, and NO were found to be significantly higher in patients with COM than in healthy controls.33 Total antioxidant capacity has been shown to be lower in the serum of individuals with COM.33
COM and Cholesteatoma
The form of COM that is characterized by the accumulation of keratinizing squamous epithelium in the air spaces of the ME or temporal bone is called COM with cholesteatoma.74 In individuals with cholesteatoma, the oxidative stress and imbalance of antioxidant enzymes were significantly elevated compared with patients with COM without cholesteatoma.75 Lipid peroxide levels in acute otitis media, cholesteatoma, and chronic discharge without cholesteatoma ranged from 575 to 650 nmol/mg of exudate, whereas the level in OME as only 67 nmol/mg in OME, a statistically significant difference.73
In one study, the serum MPO activity and the levels of MDA, 4-HNE, and NO were significantly higher in patients with cholesteatoma than in the control individuals, but the difference between the otitis media groups was not statistically significant.33 Another study confirmed the elevation of MDA in the serum of individuals with COM, both with and without cholesteatoma, compared with the serum of a control group
(P < .01); in addition, antioxidant enzymes, including SOD, catalase, and GPx, were significantly lower (P < .01).76
The researchers for that study suggested that the findings indicated that evaluating the values only of serum oxidative stress (ie, excluding an assessment of tissue values) may suffice for the evaluation of oxidative stress in COM patients.76
Tympanic Membrane Sclerosis
In individuals with tympanosclerosis, increased levels of NO in tissue and MDA levels in both the tissue and plasma have been reported.77
Tonsillitis
Tonsillitis has a number of identifying characteristics including (1) frequent attacks of tonsil infections and adenoiditis, (2) respiratory obstruction by enlarged tonsils and adenoids, and (3) chronically inflamed tonsils and adenoids with white debris coming from the crypts of tonsils. Yilmaz et al78 found that those characteristics have been accepted as indications for tonsillectomy and adenoidectomy.
Overall, very few studies have reported decreased blood levels of GSH related to tonsillitis and tonsillectomy. A study by Cvetkovic et al79 in 2009 showed that determinations of the blood levels of oxidants and antioxidants before and after tonsillectomy have shown that oxidant levels were elevated and antioxidant levels were lower prior to surgery than those of controls.
Yilmaz et al78 in 2004 found that serum antioxidants had increased and oxidant levels had decreased significantly postsurgery for patients with tonsillitis (P < .05). The Yilmaz study also found that serum GSH levels were lower in those patients compared with healthy controls prior to surgery
(P < .0001) and, postsurgery, a statistically significant increase in the levels of blood GSH had occurred for them (P < .0001). However, the levels of reduced GSH and other antioxidants did not reach those of the normal control group at 1 month postsurgery, suggesting that oxidative stress continued for more than 1 month postoperatively.78
Cvetkovic et al79 found that tonsil tissue in recurrent tonsillitis (RT) had decreased levels of GSH compared to tonsillar hypertrophy (TH) tissue; however, due to ethical constraints, no normal tonsil tissue was available for comparison. That study also found that blood-lipid peroxidation had increased significantly in TH and RT compared with that of control groups. In that study, levels of blood sulfhydryl, which include GSH, showed an increase after surgery compared with presurgical levels. The researchers had found that oxidative stress in patients with TH and RT had persisted at one month following removal of the tonsillar tissue, and they suggested that “antioxidant therapy, during the recovery period after tonsillectomy, could be an optional treatment.”79
Meniere’s Disease
Oxidative stress, a risk factor for microvascular disease, is also involved in the development of the endolymphatic hydrops that are part of the pathophysiology of Meniere’s disease.80 Increased biomarkers of protein oxidation, such as levels of protein carbonyls and 4-HNE, in addition to low GSH levels in the plasma and lymphocytes, have been identified in the individuals with Meniere’s disease compared with controls.81
Laryngeal Conditions
The anatomic position and function of the larynx as the protector of the airway, place it at risk when it comes to exposure to free radicals. In the porcine model, it has been shown that the stratified squamous epithelia of the vocal folds effectively defend against an acute ROS challenge, and it has been conjectured that GSH is present in the surface fluid that bathes the vocal folds, just as it is in the lung ELF.82 Oxidative stress has been postulated as an etiology both of laryngeal cancer83 and laryngeal aging.84
It has been shown in human tissue that phonotrauma results in increases of interleukin 1-β, tumor necrosis factor-α, prostaglandin E2, and matrix metalloproteinase 8 in the surface secretions of human tissue in vocal folds, suggesting that oxidative stress could accompany such trauma.85
Anecdotal reports have suggested that high doses of intravenous GSH can support vocalists’ ability to perform and has been observed to help resolve benign vocal-fold lesions. However, a preliminary controlled study that measured vocal dynamics in individuals given intravenous GSH or a placebo found no measurable differences between the 2 groups (e-mail communication, Benjamin Asher, MD).
Chronic Cough
A clinical study of individuals with chronic cough that was not associated with underlying pulmonary conditions has shown increased levels of 8-isoprostane, a product of peroxidation of arachidonic acid by ROS, in the exhaled breath condensate of those individuals, indicating that oxidative stress is associated with chronic cough.86
CONCLUSIONS
Many ENT conditions are associated with oxidative stress and decreased GSH, both locally in the affected tissues and systemically. The oxidative stress of those conditions may be related to depletion of GSH, which is normally increased in response to the higher levels of O2 in the upper respiratory tract. A small number of studies have reported clinical benefits from the use of an antioxidant or GSH support. The findings of benefits and the lack of reports of side effects suggest that the clinical use of antioxidants and support with GSH in ENT conditions may be considered as adjuncts to conventional management and suggest that more research is warranted.
AUTHOR DISCLOSURE STATEMENT
Benjamin F. Asher has no conflicts to disclose. Frederick T. Guilford is science officer and managing partner of Your Energy Systems, LLC.
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