The Therapeutic Effect of DA-6034 on Ocular Inflammation via Suppression of MMP-9 and Inflammatory Cytokines and Activation of the MAPK Signaling Pathway in an Experimental Dry Eye Model

Seo, Mi Jeong; Kim, Jung‐Yeul; Lee, Min Jung; Sohn, Yong Sung; Kang, Kyung Koo; Yoo, Moohi

doi:10.3109/02713680903453494

Cited by 40 publications

(28 citation statements)

References 29 publications

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“…66 We have also shown that Gelatinase B (MMP-9) was the most abundant gelatinolytic enzyme present in tears, elevated approximately twofold in eyes with pterygia versus the contralateral control eyes. 70 This may be a contributing factor 77 to the ocular surface inflammation and dry eye syndrome seen in pterygium patients 78 -perhaps presenting another therapeutic opportunity in treatment with topical cyclosporine. 79 Another potential mode of action of cyclosporine is by the inhibition of the tachykinin NK1 receptors 80 that we have localized to infiltrating fibroblasts, mononuclear cells and the epithelia of pterygia.…”

Section: Peripheral Light Focusing and Pterygium Pathogenesismentioning

confidence: 97%

Ultraviolet Radiation and the Anterior Eye

Coroneo

2011

Eye &Amp; Contact Lens: Science &Amp; Clinical Practice

112

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The eye is on the one hand dependent on visible light energy and on the other hand can be damaged by these and the contiguous ultraviolet (UV) and infrared wavelengths. Diseases of the eye in which sunlight has been implicated have been termed the ophthalmohelioses, and these conditions pose a significant problem to the eye health of many communities. The ophthalmohelioses have a tremendous impact on patients' quality of life and have significant implications on the cost of health care. Although cataract is not entirely caused by insolation, it now seems certain that sunlight plays a contributory role-cataract extraction is one of the, if not the most, commonly performed surgical procedures in many societies. Pterygium, typically afflicting a younger population, adds a tremendous burden, both human and financial, in many countries. We review evidence that peripheral light focusing by the anterior eye to the sites of usual locations of pterygium and cataract plays a role in the pathogenesis of these conditions. Recognition of the light pathways involved with foci at stem cell niches has directed our investigations into inflammatory and matrix metalloproteinase-related pathophysiologic mechanisms. An understanding of the intracellular mechanisms involved has provided some insight into how medical treatments have been developed for the effective management of ocular surface squamous neoplasia. The concept of peripheral light focusing has also provided direction in the prevention of these diseases. This has resulted in improved sunglass design and the further development of UV-blocking contact lenses. With the development of ocular UV fluorescence photographic techniques, we have been able to demonstrate preclinical ocular surface evidence of solar damage. Evidence that diet may play a role in the development of certain conditions is reviewed. The conundrum of the public health message about solar exposure is also reviewed, and in this context, the potential role of vitamin D deficiency is summarized. The eye may play a role in the development of individualized assessment techniques of solar damage, perhaps allowing us to provide better advice to both individuals and populations.

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Section: Peripheral Light Focusing and Pterygium Pathogenesismentioning

confidence: 97%

Ultraviolet Radiation and the Anterior Eye

Coroneo

2011

Eye &Amp; Contact Lens: Science &Amp; Clinical Practice

112

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“…Other possible new treatments include DA-6034 which showed therapeutic efficacy by restoring tear function and inhibiting inflammatory response in a rabbit lacrimal gland inflammation model of dry eye (Seo et al, 2010), and phosphodiesterase 4 (PDE4) inhibitors which have the potential to control ocular surface inflammation by increasing cAMP levels (Govek et al, 2010). Recently, the demonstration of corneal lymphangiogenesis in DED, associated with significant increases in expression of pro-lymphangiogenic factors VEGF-C, VEGF-D, and VEGFR-3, and the detection of increased level of VEGF in tears of patients with dry eye (Enríquez-de-Salamanca et al, 2010), have opened the potential for new therapeutic approaches.…”

Section: Strategies For Controlling Ocular Surface Inflammationmentioning

confidence: 99%

Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease

Barabino

Chen

Chauhan

et al. 2012

Progress in Retinal and Eye Research

250

180

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The tear film, lacrimal glands, corneal and conjunctival epithelia and Meibomian glands work together as a lacrimal functional unit (LFU) to preserve the integrity and function of the ocular surface. The integrity of this unit is necessary for the health and normal function of the eye and visual system. Nervous connections and systemic hormones are well known factors that maintain the homeostasis of the ocular surface. They control the response to internal and external stimuli. Our and others’ studies show that immunological mechanisms also play a pivotal role in regulating the ocular surface environment. Our studies demonstrate how anti-inflammatory factors such as the expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in corneal cells, immature corneal resident antigen-presenting cells, and regulatory T cells play an active role in protecting the ocular surface. Dry eye disease (DED) affects millions of people worldwide and negatively influences the quality of life for patients. In its most severe forms, DED may lead to blindness. The etiology and pathogenesis of DED remain largely unclear. Nonetheless, in this review we summarize the role of the disruption of afferent and efferent immunoregulatory mechanisms that are responsible for the chronicity of the disease, its symptoms, and its clinical signs. We illustrate current anti-inflammatory treatments for DED and propose that prevention of the disruption of immunoregulatory mechanisms may represent a promising therapeutic strategy towards controlling ocular surface inflammation.

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“…Importantly, a family of extracellular endoproteinases called ‘matrix metalloproteinases’ (MMPs) has been implicated in HSK [6]. The two most widely studied members of this family, MMP-2 and MMP-9 (gelatinase A and gelatinase B), are known as the primary extracellular matrix remodeling enzymes that participate in pathologic conditions of the cornea such as infection, dry eye and neovascularization [7,8,9]. However, few studies have addressed the potential link/interaction between TNF-α and MMPs in HSK.…”

Section: Introductionmentioning

confidence: 99%

TNF-α Stimulates MMP-2 and MMP-9 Activities in Human Corneal Epithelial Cells via the Activation of FAK/ERK Signaling

Yang¹,

Wang²,

Zhou

et al. 2012

Ophthalmic Res

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Aims: Herpes simplex virus type-1-induced herpes simplex keratitis (HSK) is a common immunological cornea disease. While previous studies have addressed the role of tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) in HSK, the mechanistic link between TNF-α and MMPs in the pathogenesis of HSK remains elusive. Methods: We first established a HSK mice model and measured the levels of TNF-α, MMP-2 and MMP-9 in the corneas at different time points by ELISA. Next, we employed cultured human corneal epithelial (HCE) cells as an in vitro model and performed gelatin zymography analysis. Results: We observed that the change in the TNF-α level shared a similar pattern to that of MMP-2 and MMP-9 in the HSK mice model. Furthermore, TNF-α stimulated MMP-2 and MMP-9 activities in a dose-dependent manner, but either knockdown of focal adhesion kinase (FAK) by short interference RNA or inhibition of extracellular regulated protein kinase (ERK) by chemical inhibitor could block TNF-α-stimulated MMP-2 and MMP-9 activities in vitro. Taken together, our results provide in vivo evidence that the TNF-α level is positively correlated with MMP-2 and MMP-9 levels in a HSK model and in vitro evidence that TNF-α stimulates MMP-2 and MMP-9 activities via the activation of FAK/ERK signaling in HCE cells. Conclusions: Our findings shed new light on the pathogenesis of HSK and open up new possibility of modulating the TNF-α-FAK-ERK signaling cascade to pursue therapeutic measures for HSK.

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The Therapeutic Effect of DA-6034 on Ocular Inflammation via Suppression of MMP-9 and Inflammatory Cytokines and Activation of the MAPK Signaling Pathway in an Experimental Dry Eye Model

Abstract: These results suggest that DA-6034 has the therapeutic effect in rabbit lacrimal gland inflammation model of dry eye and might be a potential treatment option for acute dry eye syndrome.

Cited by 40 publications

References 29 publications

Ultraviolet Radiation and the Anterior Eye

Ultraviolet Radiation and the Anterior Eye

Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease

TNF-α Stimulates MMP-2 and MMP-9 Activities in Human Corneal Epithelial Cells via the Activation of FAK/ERK Signaling

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