Elsevier

Biochemical Pharmacology

Volume 77, Issue 7, 1 April 2009, Pages 1117-1124
Biochemical Pharmacology

Commentary
Adenosine receptor agonists for promotion of dermal wound healing

https://doi.org/10.1016/j.bcp.2008.11.002Get rights and content

Abstract

Wound healing is a dynamic and complex process that involves a well-coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing.

Introduction

The mechanisms underlying the normal repair process, cell migration and proliferation, and extracellular matrix deposition and remodelling, have been extensively studied [1], [2], [3]. Cellular responses to inflammatory mediators, growth factors, cytokines, and to mechanical forces must be appropriate and precise in order to obtain optimum healing of a cutaneous wound. However, even during the normal process of wound healing complications can occur, including infection, thrombosis, and ischemia [4], [5]. More importantly, the orderly progression of the healing process is impaired in chronic wounds, including those due to diabetes.

Impaired wound healing is a major concern for diabetic patients because their wounds do not heal properly and are a source of major suffering and cost. Only two-thirds of diabetic foot ulcers eventually heal and up to 28% may result in amputation [6]. The pathogenesis of diabetic foot ulcers is complex and it is well recognized that a number of contributory factors working together ultimately lead to impaired healing. Several intrinsic factors, such as peripheral neuropathy, foot deformity, peripheral vascular disease and peripheral oedema have been identified as the commonest factors responsible of impaired healing after trauma. In addition, extrinsic factors, such as wound infection, callus formation, and excessive pressure to the site, further aggravate the healing process [7].

Recent studies suggest that nerves play a central role in tissue homeostasis and can orchestrate complex reparative as well as destructive processes. First, an intact nociceptor system of primary afferent sensory nerves is important for the initiation of the inflammatory process and successful tissue repair [8]. Apart from the loss of pain perception, which is a key factor in the development of neuropathic foot ulcers, loss of autonomic function and small fibre neuropathy can result in impaired neurogenic control of local microcirculatory blood flow, impaired fluid homeostasis, diminished energy metabolism, oxygen delivery, and inflammatory responses. These processes could render the feet of diabetic patients with neuropathy more susceptible to tissue damage and infection [9].

Given the complexity of the pathogenesis of diabetic foot ulcers, many different interventions have been proposed to accelerate the healing process, but few have been subjected to formal evaluation. Despite the relatively large number of studies of growth factors like PDGF (becaplermin), EGF, basic FGF and other agents modulating aspects of wound physiology, there is currently little evidence to suggest that any of the reported interventions should be adopted in routine practice. Diabetic foot ulcer management is based on the simple principles of eliminating infection, debridement, cleansing and the use of dressings to maintain a moist wound bed, and lastly, becaplermin is the only promoting agent approved for use of those ulcers resistant to simpler interventions [6].

Based in studies carried out in vitro and in experimental animal models, we are proposing a new strategy for the promotion of impaired wound healing, the use of adenosine receptor agonists. We will summarized the biology of adenosine and review its actions on different tissues and cells implicated in the healing of cutaneous wounds, as well as its effect on experimental wounds in animals.

Section snippets

Purine metabolism and biology

Adenosine is a ubiquitous purine nucleoside produced by stepwise dephosphorylation of ATP by the coordinated action of ecto-apyrase (CD39) and ecto-5′-nucleotidase (CD73) (Fig. 1). While extracellular ATP and other nucleotides (ADP, UTP and UDP) have many biological effects through direct activation of cell surface receptors for adenine nucleotides (seven P2X ionotropic and eight P2Y metabotropic receptor subtypes), adenosine modulates cellular and organ function via occupancy of four specific

Could adenosine play a role in normal wound healing?

Under basal conditions, the extracellular adenosine concentration is rather constant (30–300 nM), and held in tight check by the equilibrium between adenosine production/release into the extracellular space and adenosine uptake by cells or catabolism to inosine (Fig. 1). In contrast its concentration can increase dramatically to micromolar or even higher ranges when there is an imbalance between energy use and energy supply, such as in oxygen depletion, or under conditions of cellular or tissue

Adenosine in inflammation

Hemostasis and inflammation constitute the first phase of tissue repair. The formation of a blood clot re-establishes tissue hemostasis and provides a provisional matrix for cell migration. Released cellular mediators initiate inflammatory leukocyte recruitment necessary for removing necrotic tissue and preventing infection [1]. In addition, inflammatory cells release a variety of cytokines and chemokines that play an important role in the evolution of granulation tissue through stimulation of

Adenosine in tissue formation

Driven by growth factors synthesized by local and migratory cells, fibroblasts migrate on the provisional fibrin scaffold into the wound where they proliferate and construct a more robust collagen rich extracellular matrix. Wound fibroblasts acquire a distinctive contractile and secretory phenotype, known as myofibroblasts, responsible for wound contraction, a very important event in full thickness wounds. In response to many of the same growth factors, epidermal cells migrate from the edge of

Adenosine in neovascularization

Revascularization of the wound bed is essential to supply oxygen, nutrients, and inflammatory cells to the newly growing tissue. Two mechanisms contribute to the development of new vessels in the adult: angiogenesis, the formation of new vessels from pre-existing ones; and vasculogenesis, the initial series of events in vascular growth in which endothelial cell precursors (angioblasts) differentiate in situ and assemble into solid endothelial cords [53]. This multistep process is highly

Adenosine in remodeling

The reparative process culminates with the remodelling of the newly formed granulation tissue in order to restore complete functionality. During this extended phase, the provisional extracellular matrix rich in type 3 collagen is degraded by serine proteases and metalloproteases and sequentially substituted for the definitive matrix rich in type 1 collagen [1].

Activation of plasminogen plays a role in proteolytic degradation of extracellular matrices in tissue remodelling events and it is

Adenosine agonist promotion of wound healing in animal models

Much of the knowledge of the normal healing process of cutaneous wounds and the mediators involved has evolved from information derived from experimental wounds in animals, especially genetically modified mice. Unfortunately, a valid model of chronic wounds in animals has not yet been developed. From the in vitro experiment data it is difficult to predict which adenosine agonists, if any, will be useful for promoting impaired wound healing in humans.

There are few reports of the use of adenosine

Conclusion

Nowadays there is a high awareness of the problem that diabetic foot ulcers represent in terms of costs and quality of life for those suffering them. Studies to better understand the normal healing process and the pathology of impaired healing have been extremely useful to improve wound management and care. Randomized controlled trials have shown that topical application of becaplermin gel is effective in increasing healing rates for diabetic neuropathic foot ulcers with adequate blood supply.

Acknowledgments

MCM is beneficiary of the Ramón y Cajal program from the Spanish Government (Ministerio de Educación y Ciencia) and a grant from the Instituto de Salud Carlos III (FIS 05/1659) of the Ministry of Science and Innovation, Government of Spain. B.N.C. is a consultant for King Pharmaceuticals, Can-Fite Biopharma, Inc., Bristol-Myers, Squibb, and Tap Pharmaceuticals. He is funded by grants from King Pharmaceuticals and the National Institutes of Health (AA13336, AR41911, GM56268, and HL70952) and is

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