SB 216763 br Conclusions br Funding br Acknowledgements and

Conclusions
Funding
Acknowledgements and Disclosures We would like to thank veterinarian Angelina Williams and assistants Justin Courson, Ashutosh Jnawali, Mythri Puella, Santoshi Ramachandran, and Zhihui She for support during dissections. We also thank Drs. Vallabh Das, Deborah Otteson and Alison McDermott for their contributions. This work was supported by the National Institutes of Health grant RO1 EY03611. The funding source had no involvement in the collection, analysis, or interpretation of data. Declarations of interest: none.
Introduction Fibrosis can be described as excessive development of fibrous connective tissue, which can occur in various tissue types and organs (eg, kidney, lung, skin, and liver). At a cellular level, tissue resident quiescent fibroblasts and other SB 216763 such as endothelial, epithelial cells, and fibrocytes can differentiate into myofibroblasts, which have a crucial role in fibrosis characterized by increased proliferation, increased extra-cellular matrix (ECM) protein production, and contraction.1, 2 Moreover, their persistence (ie, failure to undergo apoptosis) and proliferation has been suggested to be one of the hallmarks of chronic fibrosis.3, 4 Peyronie’s disease (PD) is a fibrotic disorder characterized by the formation of plaques within the tunica albuginea (TA) of the penis. Although its etiology is still poorly understood, microvascular trauma has been postulated as the initiating factor. This fibrotic disorder is also characterized by the expression of several cytokines and growth factors, fibrin deposition, and myofibroblast differentiation. In PD, the myofibroblast activity is increased, resulting in increased ECM protein production and eventual plaque formation7, 8, 9, 10, 11 suggesting a pivotal role for myofibroblasts in the pathophysiology of PD. Inhibition of differentiation of quiescent fibroblasts to pro-fibrotic myofibroblasts has been suggested as a therapeutic approach for fibrosis. Accordingly, we have been investigating potential molecular targets that may be involved in myofibroblast differentiation and small molecule compounds that may inhibit this process. 1 such target that is suggested in pathophysiology of fibrosis is adenosine and its receptors. Adenosine is a ubiquitous purine nucleoside released from cells and tissues under conditions of stress or injury and is generated intra-cellularly and extra-cellularly from adenine nucleotides, which are then dephosphorylated to adenosine. CD39 and CD73 are 2 cell surface molecules responsible for catalyzing the de-phosphorylation of adenine nucleotides to adenosine in the extra-cellular space.12, 13 Adenosine regulates its effects on tissue re-generation and repair via the interaction with a family of G-protein-coupled receptors: adenosine receptor A1 (ADORA1), adenosine receptor A2A (ADORA2A), adenosine receptor A2B (ADORA2B), and adenosine receptor A3 (ADORA3). Several studies have shown that adenosine receptors play different roles in acute and chronic injuries. In acute tissue injury, adenosine has been shown to be beneficial, as it is responsible for tissue protection and anti-inflammatory responses (eg, promotion of barrier function and wound healing) in several organs, including kidney, lung, heart, and liver. In contrast to acute states, increased levels of adenosine have been associated with the progression of chronic tissue injuries. In these settings, adenosine has been suggested to promote fibrosis in several organs, such as the heart, skin, liver, lung, penis, and kidney. The adenosine receptors play different roles in the pathogenesis of fibrosis depending on the tissue subtype involved; however, the effects of adenosine are mainly regulated by ADORA2A and ADORA2B. The characterization of these receptors has been investigated in other fibrotic disorders; however, no characterization of these receptors has been carried out in PD. By understanding how adenosine receptors may regulate the response to injury in this specific tissue and by looking at the myofibroblast transformation process, it may provide new insights into the pathophysiology of fibrosis in general and in PD. Furthermore, by targeting the respective pathway and by investigating the effect of selective agonist and antagonist compounds, it may enable avenues to identify potential targets for the treatment of PD and other fibrotic disorders and enhance the resolution of the injury or halt the progression of fibrosis in PD.