This special issue of JOPT focused on purinergic signaling is dedicated to Mortimer M. Civan, MD, a prominent leader in purine research. The original concept for the issue arose during a symposium held in Mort's honor at the University of Pennsylvania in March of 2015. The symposium included collaborators that covered the breadth of Mort's career, from his years researching transport mechanisms across the kidney to his more recent investigations into the mechanisms underlying aqueous humor hydrodynamics.
Mort's initial purine work in the eye concerned the ability of P1 and P2 receptor stimulation to regulate aqueous humor production by manipulating transport mechanisms of the pigmented and nonpigmented ciliary epithelial cells. Using both cultured cells and living mice, his results showed for the first time (and against dogma) that ATP was physiologically released from the ciliary epithelial cells, that adenosine A3 receptors were major positive regulators of aqueous humor formation, and that stimulation of P2 receptors by ATP reduced aqueous humor secretion by encouraging secretion in the opposite direction. Mort then turned his attention to the conventional outflow field. His studies on outflow described the major routes for ATP release from trabecular meshwork (TM) cells involving pannexin-1 and connexin hemichannels. Importantly, he demonstrated that stretching TM cells [a mechanism by which outflow cells sense intraocular pressure (IOP) changes] increased ATP release, suggesting that purines mediate responses to elevations in IOP. Mort also documented the expression pattern and functionality of ecto-ATPases that metabolize ATP to adenosine in human TM cells. Building upon his data and the contributions of the laboratories of Craig Crosson and Ted Acott, he developed a feedback model whereby (1) elevated IOP stimulates ATP release from TM cells, (2) ATP is converted to adenosine, which increases metalloproteinase (MMP) activity of MMP-9 as well as MMP-2, and (3) increased extracellular matrix turnover decreases conventional outflow resistance and normalizes IOP. This model is being used as the basis of studies that continue today and were foundational for development of therapeutics currently in clinical trials.
Although Mort's contributions were focused on the purinergic regulation of aqueous humor production and outflow, this special issue includes work dealing with purine contributions throughout the eye. Some of the contributors collaborated closely with Mort, whereas others developed a body of work that, although fully independent, embodied the same devotion to careful investigation of receptor-mediated mechanisms that Mort himself followed. Mort showed us that it was not enough to just examine the isolated effect of stimulating a particular receptor. Instead, he continuously developed hypotheses that examined receptor function as part of a larger mechanism, linking agonist release and degradation to physiological and sometimes pathophysiological developments. However, Mort was driven by a desire to develop these findings into treatment for patients. He saw such translational approaches as a key outcome of his years of research, applying his encyclopedic knowledge of transport mechanisms to identifying drugs that lower IOP and thus help reduce the threat of vision loss for glaucoma patients. The basic approach of taking purinergic signaling from the complex receptor-dependent modifications of ion and fluid transport to developing treatments embodies many of the underlying motivations here at JOPT. As such, we dedicate this special issue to Mort Civan in recognition of his many efforts to understand the details of purinergic signaling in the eye. We hope the information provided here will encourage readers to use mechanistic approaches to develop new treatments for ocular diseases.