Aging and oxidative stress seem to have a key role in the onset and progression of ocular surface diseases.
We asked a few questions about this “hot” topic to Prof. Kazuo Tsubota of Keio University School of Medicine, Department of Ophthalmology (Tokyo), who is a leading international expert and researcher in this field.
Let us start with a general question: what is the “oxidative stress” and why is it related to biological damage?
Oxidative stress means free radical stress, which is a reactive molecule that tries to get the electron from the important proteins, lipids, DNA of the cells of the body. That is the most important stress to the human body.
What is the role of oxidative stress in the aging process and are there biological mechanisms to contrast its effects?
When the targeted molecule is oxidized (attacked by the oxidative stress), the molecule, such as enzymes, decrease or lose the function and eventually change the structure. Some of the oxidized lipids are very reactive and start a vicious cycle, producing more oxidative stress to the other tissues.
Are there validated biomarkers to measure oxidative stress and how they work?
Yes, there are many good validated biomarkers, like 8-OHdG, which is the oxidative stress biomarker for DNA. When the 8-OHdG is increased it means more oxidative stress in the tissue. Malondialdehyde (MDA) is the oxidative stress biomarker for lipid omega-3, etc.
The onset and progression of which ocular diseases can be associated with oxidative stress? Is there any difference in the “trigger” mechanism involved in the different cases?
Many ocular diseases are oxidative stress-related, such as Age-Related Macular Degeneration (ARMD) is considered to be caused by oxidative stress, so smoking, blue and UV light exposure, and high-fat diet are causing oxidative stress resulting in ARMD. Cataract is also considered to be caused by oxidative stress so UV light and lack of vitamin C are considered to be the causal factors. For the ocular surface, ptergyium, conjunctivochalasis are the oxidative stress-related diseases.
In the pathogenesis of dry eye, inflammation has a key role in the mechanism of ocular surface injury. Could you explain us the complex interaction between inflammation and oxidative stress (cause or effect)?
The initial mechanism is considered to be the same, attacking the important molecules in the cells of each tissue, but since the tissue varies, the result (disease) is different.
The ocular surface is particularly exposed to environmental agents, is this relevant for the damage induced by oxidative stress?
Yes, this is very important. The ocular surface is exposed to the air when the eye is open, when the eyes are closed or during sleep, the eye is not exposed to the air so the oxygen level varies from 150 mmHg to 55 mmHg. It is considered to be oxygen reperfusion, which is inducing a lot of free radicals. Not only the oxygen itself, the ocular surface exposed to UV light which produces a lot of oxidative stress. Also, a lot of chemicals floating in the air, such as smoke, produce ocular surface free radicals, resulting in severe inflammation.
Is cigarette smoking related to the effects of oxidative stress in dry eye?
Yes, cigarette smoking enhances the effects of oxidative stress in dry eye. My research group has several models of smoking and dry eye which show the very bad effect.
Apart from future treatments aimed at the therapeutic inhibition of oxidative stress, is there a rationale in caloric restriction in order to prevent the decline in lachrymal gland function and morphological changes associated to oxidative stress?
Yes, this is an important question. The recent review paper by Verdin’s research group reported that calorie restriction is now considered to be the major intervention for anti-aging approach. The effector phase of calorie restriction seems to be the control of mitochondrial oxidative damage. Direct control of oxidative stress as well as calorie restriction, which controls the mitochondrial oxidative stress, both of them are related to oxidative stress control.
You are among the authors of a paper recently published in Investigative Ophthalmology and Visual Science (Jan. 2013) about lipid oxidative stress status in Sjögren’s syndrome patients. Which are the most important results reported this study?
In Sjögren’s syndrome, an inflammatory immune disorder, so inflammation is the center of the disease. However, we have shown in this paper that oxidative stress is also very high so there is the possibility that the vicious cycle between the oxidative stress and inflammation is occurring in the disease process.
Not only the control of inflammation but the control of oxidative stress can be a good strategy for the treatment of Sjogren’s syndrome.
In summary, oxidative stress is related to aging itself and also, locally, to the eye, especially the ocular surface, when exposed to the environment, oxygen reperfusion, UV light, blue light, smog, smoking, and many pathogens as well as artificial contact lens. Tissues are always being attacked by oxidative stress and although the system is strong in combating the oxidative stress damage, when the system’s balance is broken, the disease condition occurs, which can be treated by oxidative stress control.
To contact Prof. Tsubota please writeto Catherine Oshima E-mail: email@example.com
Prof Kazuo Tsubota
Chairman of the Department of Ophthalmology at Keio University School of Medicine (Tokyo, Japan) and Visiting Professor, Department of Ophthalmology of Tokyo Dental College Ichikawa General Hospital (Chiba, Japan). Prof. Kazuo Tsubota is an internationally recognized dry eye specialist, who has been working on the pathogenesis and treatment of dry eye. He is currently leading many research projects which include aging, ocular surface reconstruction, regeneration of the cornea, lachrymal gland, immunology of Sjögren’s syndrome and wound healing after refractive surgery.
1. Altinors DD, Akca S, et al. (2006). Smoking associated with damage to the lipid layer of the ocular surface. Am J Ophthalmol 141(6): 1016-1021.
2. Higuchi A, Ito K, et al. (2011). Corneal damage and lacrimal gland dysfunction in a smoking rat model. Free Radic Biol Med 51(12): 2210-2216.
3. Ibrahim OM, Kojima T, et al. (2012). Corneal and retinal effects of ultraviolet-B exposure in a soft contact lens mouse model. Invest Ophthalmol Vis Sci 53(4): 2403-2413.
4. Kojima T, Wakamatsu TH, et al. (2012). Age-related dysfunction of the lacrimal gland and oxidative stress: evidence from the cu, zn-superoxide dismutase-1 (sod1) knockout mice. Am J Pathol 180(5): 1879-1896.
5. Matsumoto Y, Dogru M, et al. (2008). Alterations of the tear film and ocular surface health in chronic smokers. Eye 22(7): 983.
6. Merksamer PI, Liu Y, et al. (2013). The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY) 5(3): 144-150.
7. Rummenie VT, Matsumoto Y, et al. (2008). Tear cytokine and ocular surface alterations following brief passive cigarette smoke exposure. Cytokine 43(2): 200-208.
8. Wakamatsu TH, Dogru M, et al. (2010). Evaluation of lipid oxidative stress status and inflammation in atopic ocular surface disease. Mol Vis 16: 2465-2475.
9. Wakamatsu TH, Dogru M, et al. (2013). Evaluation of lipid oxidative stress status in sjogren syndrome patients. Invest Ophthalmol Vis Sci 54(1): 201-210.
10. Ward SK, Wakamatsu TH, et al. (2010). The role of oxidative stress and inflammation in conjunctivochalasis. Invest Ophthalmol Vis Sci 51(4): 1994-2002.
11. Ward SK, Dogru M, et al. (2010). Passive cigarette smoke exposure and soft contact lens wear. Optom Vis Sci 87(5): 367-372.