Beta2-adrenergic receptor signaling mediates corneal epithelial wound repair.
OBJECTIVE
Beta-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 beta-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 beta2-AR(+/+) and beta2-AR(-/-) mice. Signaling pathways were evaluated by immunoblotting. results. The beta-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 beta-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 beta2-AR(-/-) mice; all treatment groups showed statistically equivalent migratory speeds and ERK phosphorylation. In beta2-AR(+/+) animals, the beta-AR agonist (isoproterenol) delayed the rate of in vivo corneal wound healing by 79%, whereas beta-AR antagonist (timolol) treatment increased the rate of healing by 16% (P < 0.05) compared with saline-treated controls. In contrast, in the beta2-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 beta2-AR for the modulation of corneal epithelial wound repair.
Ghoghawala
Shahed Y
SY
Department of Ophthalmology and Vision Science, School of Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Mannis
Mark J
MJ
Pullar
Christine E
CE
Rosenblatt
Mark I
MI
Isseroff
R Rivkah
RR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D004837:Epinephrine / Q000378:metabolism; D019573:Epithelium, Corneal / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013999:Timolol / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018343:Receptors, Adrenergic, beta-2; D013999:Timolol; D014446:Tyrosine 3-Monooxygenase; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; D004837:Epinephrine