IOVS European Journal of Biochemistry
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(Investigative Ophthalmology and Visual Science. 2008;49:1857-1863.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0925
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β2-Adrenergic Receptor Signaling Mediates Corneal Epithelial Wound Repair

Shahed Y. Ghoghawala,1 Mark J. Mannis,2 Christine E. Pullar,3,4 Mark I. Rosenblatt,2 and R. Rivkah Isseroff3,5

1From the School of Medicine, and the 2Departments of Ophthalmology and Vision Science and 3Dermatology, University of California-Davis, Davis, California, and 5the Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Mather, California.

PURPOSE. β-Adrenergic receptor (AR) antagonists are frequently prescribed ophthalmic drugs, yet previous investigations into how catecholamines affect corneal wound healing have yielded conflicting results. With the use of an integrated pharmacologic and genetic approach, the authors investigated how the β-AR impacts corneal epithelial healing.

METHODS. Migratory rates of cultured adult murine corneal epithelial (AMCE) cells and in vivo corneal wound healing were examined in β2-AR+/+ and β2-AR–/– mice. Signaling pathways were evaluated by immunoblotting.

RESULTS. The β-AR agonist isoproterenol decreased AMCE cell migratory speed to 70% of untreated controls, and this was correlated with a 0.60-fold decrease in levels of activated phospho-ERK (P-ERK). Treatment with the β-AR antagonist (timolol) increased speed 33% and increased P-ERK 2.4-fold (P < 0.05). The same treatment protocols had no effect on AMCE cells derived from β2-AR–/– mice; all treatment groups showed statistically equivalent migratory speeds and ERK phosphorylation. In β2-AR+/+ animals, the β-AR agonist (isoproterenol) delayed the rate of in vivo corneal wound healing by 79%, whereas β-AR antagonist (timolol) treatment increased the rate of healing by 16% (P < 0.05) compared with saline-treated controls. In contrast, in the β2-AR–/– mice, all treatment groups demonstrated equivalent rates of wound healing. Additionally, murine corneal epithelial cell expressed the catecholamine-synthesizing enzyme tyrosine hydroxylase and detectable levels of epinephrine (184.5 pg/mg protein).

CONCLUSIONS. The authors provide evidence of an endogenous autocrine catecholamine signaling pathway dependent on an intact β2-AR for the modulation of corneal epithelial wound repair.






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Copyright © 2008 by the Association for Research in Vision and Ophthalmology