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Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype

Abstract

The glaucomas are a group of optic neuropathies comprising the leading cause of irreversible blindness worldwide. Elevated intraocular pressure due to a reduction in normal aqueous outflow is a major causal risk factor. We found that endothelial leukocyte adhesion molecule-1 (ELAM-1), the earliest marker for the atherosclerotic plaque in the vasculature, was consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes with glaucomas of diverse etiology. We determined expression of ELAM-1 to be controlled by activation of an interleukin-1 (IL-1) autocrine feedback loop through transcription factor NF-κB, and activity of this signaling pathway was shown to protect TM cells against oxidative stress. These findings characterize a protective stress response specific to the eye's aqueous outflow pathways and provide the first known diagnostic indicator of glaucomatous TM cells. They further indicate that common mechanisms contribute to the pathophysiology of the glaucomas and vascular diseases.

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Figure 1: Immunohistochemical screen for CAMs altered in outflow pathways of glaucomatous eyes.
Figure 2: Regulation of ELAM-1 expression by exogenous and endogenous IL-1.
Figure 3: NF-κB activity in normal and glaucomatous TM cells.
Figure 4: Active NF-κB in glaucomatous TM cells in situ.
Figure 5: Resistance of normal and glaucomatous trabecular meshwork cells to apoptosis in response to an oxidant, and protective role of IL-1 and NF-κB.

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Acknowledgements

We thank members of the Schuman and Fini labs for their technical assistance. Some surgical specimens were provided by the Institute of Ophthalmology & Eye Hospital, Shandong Academy of Medical Science, and the Department of Ophthalmology, Wuhan Municipal First Hospital, P.R. China. The ELAM-1 cDNA was a gift from B. Seed and the GAPDH cDNA was a gift from R. Allen. This work was supported by the Glaucoma Foundation, New York (J.S.S.), the American Health Assistance Foundation (J.S.S.), NEI grant EY09828 (M.E.F.), the Massachusetts Lions Eye Research Fund and Research to Prevent Blindness.

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Correspondence to Joel S. Schuman.

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Wang, N., Chintala, S., Fini, M. et al. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. Nat Med 7, 304–309 (2001). https://doi.org/10.1038/85446

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