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Bruce Cronstein M.D.
Dr. Paul R. Esserman Professor of Medicine, Professor of Pathology and Pharmacology
Physiology and Pharmacology of Adenosine Receptors
Research Summary
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.
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. Thus, adenosine A2A receptor agonists may be useful in stimulating wound healing.
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.
Current research in the laboratory is focused on understanding the molecular mechanisms by which adenosine concentrations are increased in the extracellular space and how adenosine and its receptors regulate inflammation, wound healing and fibrosis.
Related Documents
Adenosine Receptors and Wound Healing
Recent studies have demonstrated that application of topical adenosine A2A receptor
agonists promotes more rapid wound closure and clinical studies are currently underway
to determine the utility of topical A2A adenosine receptor agonists in the therapy of
diabetic foot ulcers. The effects of adenosine A2A receptors on the cells and tissues of
healing wounds have only recently been explored. We review here the known effects of
adenosine A2A receptor occupancy on the cells involved in wound healing.
Molecular action of methotrexate in inflammatory diseases
Despite the recent introduction of biological response modifiers and potent new small-molecule
antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory
arthritis. Although methotrexate was first introduced as an antiproliferative agent that inhibits the
synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that many of the antiinflammatory
effects of methotrexate are mediated by adenosine. This nucleoside, acting at one or more
of its receptors, is a potent endogenous anti-inflammatory mediator. In confirmation of this mechanism of
action, recent studies in both animals and patients suggest that adenosine-receptor antagonists, among
which is caffeine, reverse or prevent the anti-inflammatory effects of methotrexate.
Adenosine: an endogenous regulator
Although inflammatory and immunological reactions
protect the host from invasion by microorganisms and
eliminate debris at sites of tissue injury, they can also
be responsible for significant tissue damage. Thus,
regulatory mechanisms that limit damage from an
overly exuberant immune response have evolved. It is
increasingly apparent that adenosine, a purine nucleoside
that is elaborated at injured and inflamed sites,
has a central role in the regulation of inflammatory
responses and in limiting inflammatory tissue destruction.
Adenosine, called a `retaliatory metabolite?
because it is a regulatory autocoid that is generated as
a result of cellular injury or stress, interacts with
specific G protein-coupled receptors on inflammatory
and immune cells to regulate their function. The effects
of adenosine, acting at its receptors, on the functions of
the cells that mediate innate immune responses, will be
reviewed.
Related Images
Proposed mechanism for the anti-inflammatory effects of methotrexate and sulfasalazine adenosine release diminishes leukocyte function.
Research Information
Research Interests
Adenosine-mediated regulation of inflammation, wound healing, fibrosis and bone resorption and the pharmacology of adenosine receptors
Research Keywords
adenosine, adhesion, inflammation, neutrophil, wound healing
