Adenosine is released from most cells and tissues as a result of ATP catabolism in response to such stresses as hypoxia and inflammatory injury. Adenosine regulates numerous physiologic functions via interaction with one or more of at least four known receptors (A1, A2A, A2B, A3), all of which are members of the family of G protein-coupled receptors. At least one adenosine receptor type, and generally more than one type, is expressed on nearly every cell type and tissue examined. We first demonstrated the presence and function of both A1 and A2 adenosine receptors on human polymorphonuclear leukocytes and their critical role in regulating inflammation. In more recent studies we have shown that adenosine, acting at its receptors, mediates the antiinflammatory effects of methotrexate, the most commonly used drug in the treatment of Rheumatoid Arthritis.
My laboratory continues to explore the mechanism by which adenosine receptors modulate cellular functions and regulate tissue and organ function. Inflammation is a critical first step in dealing with tissue injury and for preventing superinfection at wounded sites. Because inflammation is the first step in wound healing we asked whether adenosine receptor agonists might promote wound healing. We have demonstrated that topical application of adenosine A2A receptor agonists stimulates more rapid wound healing, a phenomenon we have helped take into the clinic where an adenosine A2A receptor agonist is undergoing clinical trials for the promotion of healing of diabetic foot ulcers. We have explored the mechanism by which adenosine A2A receptor agonists promote wound healing and found that occupancy of A2A receptors by adenosine or its more selective and potent agonists promotes new blood vessel formation and new matrix formation by fibroblasts.
Because adenosine A2A receptor agonists stimulate more rapid and exuberant wound healing we determined whether adenosine A2A receptors were involved in scar formation although the scarring we examined was in the liver. We found that adenosine A2A receptors play a critical role in animal models of liver fibrosis and that agents that block these receptors could be used to block the development of liver cirrhosis/fibrosis, an important public health problem. Moreover, adenosine and its receptors play a role in scarring and radiation fibrosis as well. We are currently continuing to investigate the role of adenosine and its receptors in pathologic fibrosis.
In other studies we have examined the role of adenosine and its receptors in bone and joint physiology and pharmacology. We have reported that adenosine A1, A2A and A2B receptors regulate bone formation and more recently have reported that adenosine receptor agonists and agents that increase local adenosine concentrations can be used to promote bone regeneration. More recently we have found that endogenously generated adenosine plays a critical role in maintaining cartilage and chondrocyte homeostasis and that agents that ligate adenosine receptors in cartilage can prevent the development of osteoarthritis.
Dr. Paul R. Esserman Professor of Medicine, Department of Medicine
Professor, Department of Pathology
Professor, Department of Biochemistry and Molecular Pharmacology
Director Program in Collaborative Research
Director, Clinical and Translational Science Institute
Director, Division of Translational Medicine
MD from University Of Cincinnati
Fellowship, New York University School of Medicine, Rheumatology
Residency, Lenox Hill Hospital, Internal Medicine
Residency, University of Cincinnati Medical Center, Internal Medicine
Residency, New York University School of Medicine, Pathology
Tissue & cell. 2017 Jul 4; ?-?
American journal of pathology. 2017 Jun 28; 187(9):1935-1944
Nature communications. 2017 May 11; 8:15019-15019
Adenosine generation limits radiation-induced tumor immunogenicity by abrogating recruitment and activation of CD103 DCs [Meeting Abstract]
Journal of immunology (1950). 2017 May; Conference:(104th):
Nature reviews. Rheumatology. 2017 Jan; 13(1):41-51
Diabetes. 2016 Dec; 65(12):3598-3609
Purinergic signalling. 2016 Dec; 12(4):583-593
FASEB journal. 2016 Nov; 30(11):3835-3844