Valentin Navel,1,2 Frédéric Chiambaretta,1,2 Christophe Baudouin,3 Frédéric Dutheil.4

1 University Hospital of Clermont-Ferrand, CHU Clermont-Ferrand, Ophthalmology, F-63000 Clermont-Ferrand, France
2 Université Clermont Auvergne, CNRS UMR 6293, INSERM U1103, Genetic Reproduction and Development Laboratory (GReD), Translational Approach to Epithelial Injury and Repair Team, F-63000 Clermont-Ferrand, France
3 Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, IHU FOReSIGHT, F-75012 Paris, France.
4 Université Clermont Auvergne, CNRS, LaPSCo, Physiological and Psychosocial Stress, CHU Clermont-Ferrand, University Hospital of Clermont-Ferrand, Preventive and Occupational Medicine, Witty Fit, F-63000 Clermont-Ferrand, France
*Correspondence: Valentin Navel, University Hospital of Clermont-Ferrand, CHU Clermont-Ferrand, Ophthalmology, valentin.navel@hotmail.fr

Dry Eye Disease (DED) is a multifactorial disease affected by age, sex, hormonal status, leisure and occupational activities (i.e. air conditioning and working at a visual display terminal), geographic zones (i.e. climate and humidity rate), duration of use of preserved topical medications, and several other ocular or systemic conditions (e.g. dopamine dysregulation in Parkinson’s disease, lid abnormalities and glaucoma). The definition of DED has been recently revamped as an inflammatory disease involving all components of the ocular surface, with an increase in tear film osmolarity and instability and a disturbance of the lacrimal functional unit, with neurogenic corneal abnormalities [1–3]. As the first-line barrier of the eye against the environment, the ocular surface is exposed daily to the intense burden of free radical stress through environmental pollution, diesel exhaust, solar ultraviolet radiation, indoor pollution, and mitochondrial sources of radical species derived from oxygen (ROS) [4,5]. However, dysregulation of oxidative stress homeostasis has not been described in the classical definition of DED.

The Ocular Surface: a first-line barrier tissue.

Resulting in discomfort and visual disturbance, DED is a growing health problem around the world. The ocular surface, particularly the cornea, is significantly affected as DED progresses, with several pathological patterns such as keratoconjunctivitis sicca, superficial punctate keratitis, and filamentous keratitis. Considering cellular apoptosis (i.e. epithelial cells of the cornea, goblet cells, and acini of secretory glands) and tissue damage under conditions of tear film hyperosmolarity [6], it has been established that a vicious circle of inflammation affects the ocular surface in DED, causing sustained symptoms, an increase in clinical severity, and neurogenic pain [7]. However, integrity of the ocular surface in diurnal mammals is crucial to eliminate oxidative stress markers accumulated during daily environmental exposure (i.e. fossil fuel exhaust, tobacco smoke, mitochondrial metabolism, UV radiation) [8]. In healthy subjects, antioxidants are particularly abundant in the tear film, aqueous humor, and corneal tissues, reducing or preventing dysregulation of redox homeostasis [8,9]. As an avascular tissue, the cornea is particularly dependent on detoxifying systems within the ocular surface and is predisposed to mitochondrial dysfunction [5]. Resulting in mutations in mitochondrial DNA, the oxidative stress induced by environmental insults might alter repair mechanisms, increase the transcription rates of mtDNA, decrease the protective levels of histone proteins, and finally generate a greater amount of ROS in corneal tissues [5]. Furthermore, leisure or occupational environmental exposures are intimately linked with urban areas and oxidative stress and are factors in the increasing prevalence of DED; working at visual display terminals, using smartphones, physical inactivity, environmental pollution mediated by fossil fuel and particulate matter, tobacco smoke, or confined spaces with air conditioning may thus play important roles in encouraging DED [2,4] (Figure 1).

Oxidative stress imbalance in DED

In a systematic review and meta-analysis, we highlighted the concept that this imbalance between oxidative stress and antioxidants appears to be a central process in the pathophysiology of DED [10]. We noted that oxidative stress markers (particularly lipid peroxide (LPO), myeloperoxidase (MPO), nitric oxide synthase 3 (NOS3), xanthine oxidase/oxidoreductase, 4-hydroxy-2-nonenal (4HNE), malondialdehyde (MDA), and ROS) were significantly increased in DED compared to healthy controls (Figure 2). In addition, we emphasized that two major components of the ocular surface showed loss of redox homeostasis in DED, namely the tear film and conjunctival cells. Neither the diagnosis of Sjögren’s syndrome nor geographical origin seemed to affect the redox imbalance in the included populations, except for antioxidants in tears of DED patients without Sjögren’s syndrome. While aging decreases the antioxidant defences of the ocular surface [11], meta-analysis showed no influence of age in oxidative stress homeostasis. Furthermore, the prevalence of DED increases in the elderly population with several ocular diseases such as glaucoma, necessitating long-term multidose eye drops with antimicrobial preservative solutions [12,13]. The most commonly used quaternary ammonium, benzalkonium chloride (BAK), induces cellular toxicity and mitochondrial changes, ROS production and a decrease in antioxidants such as glutathione peroxidase in the tissues of the ocular surface [13]. The use of BAK in ocular medications could explain the incidence of iatrogenic dry eye in chronic eye diseases, especially in the elderly, and would be inappropriate in DED, where the surface is already subject to intense oxidative stress [14]. In light of these results, we could hypothesize that loss of oxidative stress homeostasis appears to be a key factor in the pathophysiology of DED, as a starting point of the vicious circle in addition to desiccating stress and tear film hyperosmolarity and aggravation of the inflammatory cascade in ocular surface tissues. Altogether, these new findings in the pathophysiology of DED could revolutionize future systemic or topical therapies.

Antioxidant treatments in DED

DED is a chronic ocular condition, often requiring long-term treatment. Furthermore, older people appear to have a lower level of antioxidants in the tears than younger subjects, predisposing this fragile population to more severe forms of DED [11]. Thus, there is a need for novel management strategies in DED, exploring new therapeutic possibilities. In recent decades, several studies have described the antioxidant effects of trehalose, a nonreducing disaccharide naturally absent in mammals or other vertebrates [15,16]. With similar functions as a molecular chaperone, trehalose might promote the expression of nuclear factor erythroid 2-related factor 2 (NFE2L2), protecting mitochondria from oxidative damage [15,17]. Similarly, high levels of lactoferrin (physiologically produced by the lacrimal glands) in tears appear to have protective effects against UV radiation and oxidative stress. Other studies have also highlighted an improvement in both objective and subjective dry eye symptoms with antiaging and lifestyle-intervention approaches involving physical activity and dietary therapy [18–20]. The basis for these non-pharmacological therapies in DED is similar to those applied in diabetes and metabolic syndrome to reduce oxidative stress [21]. Among many others, all of these compounds and innovative treatments demonstrate that dry eye management is currently moving toward including the correction of oxidative stress imbalance, a central process in the pathophysiology of DED.

References

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Figure 1. Oxidative stress imbalance in DED. DNA: Deoxyribonucleic acid; IL: interleukin; MMP: Matrix metalloproteinases; TGF: Tumor growth factor; TNF: Tumor necrosis factor; UV: Ultraviolet.
 

Figure 2. Summary of meta-analysis on oxidative stress markers in DED compared with healthy controls, stratified by type of marker, type of sample (tears or conjunctiva), type of ocular surface sample (tears, conjunctival cells, or conjunctival tissues), Sjögren’s syndrome (DED patients with or without Sjögren’s syndrome), and geographic zone (Asia or Europe) (from ref. 10). The Weight column is the weight of each study/stratification within the meta-analysis; weight is the inverse of the estimates' variance, so that larger studies tend to contribute more than smaller studies.