Abstract
Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP immunoreactivity is co-localized with a neuronal marker, and PACAP receptor (PAC1-R) immunoreactivity is observed in mouse infraorbital lacrimal gland acinar cells. PACAP eye drops stimulate tear secretion and increase cAMP and phosphorylated (p)-protein kinase A levels in the infraorbital lacrimal glands that could be inhibited by pre-treatment with a PAC1-R antagonist or an adenylate cyclase inhibitor. Moreover, these eye drops suppress corneal keratinization in PACAP-null mice. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane and pAQP5 levels in the infraorbital lacrimal glands. AQP5 siRNA treatment of the infraorbital lacrimal gland attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder.
Highlights
Dry eye syndrome is caused by a reduction in the volume or quality of tears
On examination of this pathology, we discovered that the corneal epithelial cells were hypertrophied and the surface was keratinized (Fig. 1d)
To determine the pathway related to pituitary adenylate cyclase-activating polypeptide (PACAP)-induced tear secretion, we investigated the signalling pathways downstream of PAC1-R, focusing on the adenylate cyclase (AC)-cAMP-dependent pathway
Summary
Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. To investigate the function of PACAP in the lacrimal gland, PACAP38 was delivered in the form of eye drops to wild-type mice, and the level of tear secretion was measured using the cotton thread method (Fig. 3a). When corneas were pre-treated with the topical anaesthetic Benoxil to suppress the corneal reflex, the basal lacrimation level decreased, but PACAP still elicited a significant increase in tear secretion (Supplementary Fig. 8).
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