Alpha-1 Adrenergic Receptor Stimulation Induces Ocular Disease via TGF-Beta-Mediated Mechanisms

Abstract

Purpose: : Previously we demonstrated that stimulation of alpha-1 adrenergic receptors (A1AR) in the eye leads to the up-regulation of transforming growth factor beta (TGFB) in various local tissues. The work reported here aimed to investigate the potential clinical implications of this finding.

Methods: : Methods: We studied the effect A1AR stimulation on murine endotoxin induced uveitis (EIU), a well-known animal model of acute ocular inflammation. EIU was investigated under conditions of pharmacological A1AR stimulation and blockade, as well as in mice that had undergone ocular sympathetic denervation via the surgical removal of the superior cervical ganglion (SCGX). Inflammation was quantified by histology (H&E), flow cytometry of ocular tissue homogenates (CD45 and CD11b), and by alterations in total aqueous humor protein at the peak of the inflammatory response. Because increased TGF beta levels are routinely found in glaucomatous eyes, we also tested whether chronic A1AR stimulation could result in elevated intraocular pressure (IOP), and glaucoma-like pathology. Finally, we also examined the importance of increased TGFB levels in A1AR-mediated pathology by performing experiments in thrombospondin-1 (TSP-1) null mice, which fail to activate intraocular TGF-B.

Results: : Results: EIU was significantly and consistently exacerbated by A1AR agonist treatment as reflected by histological changes, increased inflammatory markers, and increased levels of total AH protein. This increased inflammatory process could be attenuated significantly by dose-dependent pharmacological blockade of relevant adrenergic receptors. Both A1AR blockade alone, and SCGX alone resulted in attenuated forms of EIU. In addition, chronic A1AR stimulation induced sustained IOP elevations in association with increased collagen type IV expression in anterior segment tissues. Neither of these effects could be reproduced in TSP-1 null mice.

Conclusions: : These results uncover a new and paradoxical pro-inflammatory role for both A1ARs and TGFB in acute ocular inflammation. Furthermore, they strongly suggest that chronic stimulation of A1AR may increase IOP in diseases such as glaucoma through TGFB-mediated mechanisms.

Keywords: intraocular pressure • pathobiology • uveitis-clinical/animal model