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Paola A. Durand, Yaohong Tan, Darakshan Fatmi, Xiaomei Xia, Egla Suarez, Victor L. Perez, Jose L. Vega; Alpha-1 Adrenergic Stimulation Exacerbates Acute Ocular Inflammation Through A Mechanism Mediated By Transforming Growth Factor Beta (TGFB). Invest. Ophthalmol. Vis. Sci. 2012;53(14):6235.
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Previously we demonstrated that ocular immune privilege is abolished by the surgical transection of ocular sympathetic nerves. Here we investigated the effect of sympathetic adrenergic neurotransmission on acute ocular inflammation.
The selective alpha-1 adrenergic receptor (A1AR) agonist PHE (5%) was applied every 8h for 24h to the ocular surface of mice afflicted with endotoxin-induced uveitis. In some experiments topical prazosin (PRAZ), an A1AR blocker, was applied concomitantly in order to test the specficity of A1AR-mediated effects. Inflammation was quantified by flow cytometry of digested ocular homogenates using antibodies against cell surface markers known to appear in the context of acute inflammatory responses. Total aqueous humor protein quantification (via Bradford assay), and H&E staining were also performed to further characterize inflammation in EIU. In addition, we tested the effect of A1AR stimulation on neutrophilic infiltration following syngeneic corneal transplantation of C57BL/6 mice, also by performing flow cytometry of corneal graft homogenates. Finally, because A1AR stimulation increases transforming growth factor beta (TGFB), we then tested the potential pro-inflammatory role of this TGFB increase by carrying out EIU experiments on PHE-treated TSP-1 null mice, which exhibit a failure in TGFB activation.
A1AR stimulation with topical PHE induced dramatic exacerbations of EIU, as reflected by flow cytometry, histology, and bradford assay results. These exacerbated responses could be completely prevented by co-treatment with topical PRAZ, which also significantly alleviated EIU in mice not treated with PHE. Topical PHE also led to a significant increase in neutrophilic infiltration of syngeneic corneal grafts. TSP-1 null mice exhibited similar EIU responses by comparison with wildtype mice, and did not experience detectable exacerbations after PHE treatment.
Local A1AR stimulation exacerbates acute ocular inflammation via an effect that appears to involve TGFB expression, and function.
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