Oxidative Stress Induced Inflammation Initiates Functional Decline of Tear Production

Uchino, Yuichi; Kawakita, Tetsuya; Miyazawa, Masaki; Ishii, Takamasa; Onouchi, Hiromi; Yasuda, Kayo; Ogawa, Yoko; Shimmura, Shigeto; Ishii, Naoaki; Tsubota, Kazuo

doi:10.1371/journal.pone.0045805

Cited by 115 publications

(85 citation statements)

References 44 publications

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“…The structure of the osmolyte erythritol was found to resemble mannitol, a well-known antioxidant, 47 and oxidative damage has been implicated in the pathogenesis and development of dry eye. 48,49 And recently, L-carnitine was found to protect the corneal epithelial cells from apoptosis induced by hyperosmotic stress. 50 Betaine, a metabolite of plant and animal tissues, is considered a protectant against salt and temperature stress in plants.…”

Section: Discussionmentioning

confidence: 99%

Effects ofl-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress

Hua

Deng

et al. 2014

Current Eye Research

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Purpose To explore the effects of osmoprotectants on pro-inflammatory mediator production in primary human corneal epithelial cells (HCECs) exposed to hyperosmotic stress. Methods HCECs cultured in iso-osmolar medium (312mOsM) were switched to hyperosmotic media with or without prior incubation with 2–20mM of L-carnitine, erythritol or betaine for different time periods. The mRNA expression and protein production of pro-inflammatory markers in HCECs were evaluated by RT-qPCR and ELISA. Results Hyperosmolar media significantly stimulated the mRNA and protein expression of pro-inflammatory cytokines, TNF-α, IL-1β and IL-6, and chemokines, IL-8, CCL2 and CCL20 in HCECs in an osmolarity dependent manner. The stimulated expression of these pro-inflammatory mediators was significantly but differentially suppressed by L-carnitine, erythritol or betaine. L-carnitine displayed the greatest inhibitory effects and down-regulated 54–77% of the stimulated mRNA levels of TNF-α (down from 12.3 to 5.7 fold), IL-1β (2.2 to 0.9 fold), IL-6 (7.3 to 2.9 fold), IL-8 (4.6 to 2.0 fold), CCL2 (15.3 to 3.5 fold) and CCL20 (4.1 to 1.5 fold) in HCECs exposed to 450mOsM. The stimulated protein production of TNF-α, IL-1β, IL-6 and IL-8 was also significantly suppressed by L-carnitine, erythritol and betaine. L-carnitine suppressed 49–79% of the stimulated protein levels of TNF-α (down from 81.3 to 17.4pg/ml), IL-1β (56.9 to 29.2pg/ml), IL-6 (12.8 to 4.6ng/ml), and IL-8 (21.2 to 10.9ng/ml) by HCECs exposed to 450mOsM. Interestingly, hyperosmolarity stimulated increase in mRNA and protein levels of TNF-α, IL-1β and IL-6 were significantly suppressed by a TRPV1 activation inhibitor capsazepine. Conclusions L-carnitine, erythritol and betaine function as osmoprotectants to suppress inflammatory responses via TRPV1 pathway in HCECs exposed to hyperosmotic stress. Osmoprotectants may have efficacy in reducing innate inflammation in dry eye disease.

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Section: Discussionmentioning

confidence: 99%

Effects ofl-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress

Hua

Deng

et al. 2014

Current Eye Research

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“…161 Infiltration with autoreactive T cells and oxidative stress have also been observed in the aged lacrimal gland, indicating that aging is associated with inflammation and is not simply a degenerative process. 98, 137, 162–166 These studies suggest that similar to the ocular surface, a vicious cycle of inflammation and apoptosis involving infiltrating cells and glandular acinar cells perpetuates LG inflammation leading to glandular dysfunction in SS and age-related dry eye.…”

Section: Dry Eye – a Multifactorial And Self-perpetuating Inflammatormentioning

confidence: 98%

The Pathophysiology of Dry Eye Disease

2017

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Clinical and laboratory studies performed over the past few decades have discovered that dry eye is a chronic inflammatory disease that can be initiated by numerous extrinsic or intrinsic factors that promote an unstable and hyperosmolar tear film. These changes in tear composition, in some cases combined with systemic factors, lead to an inflammatory cycle that causes ocular surface epithelial disease and neural stimulation. Acute desiccation activates stress signaling pathways in the ocular surface epithelium and resident immune cells. This triggers production of innate inflammatory mediators that stimulate the production of matrix metalloprotease, inflammatory cell recruitment, and dendritic cell maturation. These mediators combined with exposure of autoantigens can lead to an adaptive T-cell mediated response. Cornea barrier disruption develops by protease-mediated lysis of epithelial tight junctions leading to accelerated cell death, desquamation, an irregular poorly lubricated cornea surface and exposure and sensitization of epithelial nociceptors. Conjunctival goblet cell dysfunction and death are promoted by the T helper 1 cytokine interferon gamma (IFN-γ). These epithelial changes further destabilize the tear film, amplify inflammation and create a vicious cycle. Cyclosporine and lifitegrast, the two FDA-approved therapies inhibit T cell activation and cytokine production. While these therapies represent a major advance in dry eye therapy, they are not effective in improving discomfort and corneal epithelial disease in all patients. Preclinical studies have identified other potential therapeutic targets, biomarkers and strategies to bolster endogenous immunoregulatory pathways. These discoveries will hopefully lead to further advances in diagnostic classification and treatment.

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“…oxidative stress models to confirm the relationship between ROS and dry eye. 48 Tobacco smoking is believed to be a risk factor for dry eye, and it may be attributable to oxidative stress. Clinical studies have shown that tobacco smoking induces ROS in the ocular surface by initiating inflammation, resulting in dry eye.…”

Section: Oxidative Stress and Dry Eyementioning

confidence: 99%

The Antiaging Approach for the Treatment of Dry Eye

Tsubota

Kawashima

Inaba

et al. 2012

Cornea

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Dry eye is one of the most common eye disorders affecting millions of people. It causes ocular irritation or discomfort, and decreases functional vision, causing a dramatic deterioration in the quality of life. Although new treatments such as the P2Y2 agonist or cyclosporine eye drops have been developed and a certain level of patient satisfaction can now be obtained, no fundamental treatment has been developed. Currently, there is no therapy available to recover lacrimal function to its normal status. Recent progress in the understanding of aging has laid the foundations for a new way of thinking about intervention of the aging process. Because dry eye is accelerated by aging, a useful approach for the prevention or treatment of dry eye may be to interfere with the aging process. In the scientific community, there is a global consensus that calorie restriction can extend the life span of various kinds of animals, establishing an intervention to aging. Another important hypothesis believed to be involved in aging is the free radical theory. According to these theories, the aging process may be managed by controlling levels of calories or reactive oxygen species. In this review, these 2 important aging theories, calorie restriction and free radical aging, are examined, and we discuss how to apply these theories to the prevention and treatment of dry eye.

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Oxidative Stress Induced Inflammation Initiates Functional Decline of Tear Production

Cited by 115 publications

References 44 publications

Effects ofl-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress

Effects ofl-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress

The Pathophysiology of Dry Eye Disease

The Antiaging Approach for the Treatment of Dry Eye

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