Introduction

Although humans and other mammals have lost, for the most part, the ability to regenerate injured tissue, the capacity to heal wounds is of critical importance for restoring function and, in the skin, maintaining a barrier against the external environment. The processes involved in wound healing include cleaning up the damaged tissue and preventing tissue invasion by microorganisms (inflammation), rebuilding the vascular network in the wounded site and creating a scaffold of connective tissue (granulation tissue formation), surfacing the wound (re-epithelialization), and a much slower process of re-organization of the scar. In some people, such as individuals with diabetes or venous stasis, the process goes awry and the wounds do not heal in a timely fashion or at all. Although tissue repair is effective in re-establishing a barrier, the wound healing process may lead to scarring, fibrosis, and loss of function (as in the case of contractures). Internal organs may similarly be scarred and the fibrosis and loss of architectural integrity may lead to significant organ dysfunction. Moreover, some illnesses, such as scleroderma, are characterized by pathologic fibrosis of the skin and/or internal organs resulting in diffuse skin fibrosis and internal organ dysfunction. Many other ailments, such as liver cirrhosis, may lead to specific organ destruction with resulting fibrosis, scarring, and loss of function.

A variety of factors regulate the wound healing process, ranging from growth factors to small molecules released at the wounded site. One such factor is adenosine, a ubiquitous purine nucleoside that is generated in the extracellular space by dephosphorylation of adenine nucleotides released by cells as a result of metabolic factors, injury, and hypoxia (Figure 1). Adenosine mediates its effects on tissue regeneration and repair via binding and activation of a family of G protein-coupled receptors (adenosine A₁, A_2A, A_2B, and A₃ receptors). In this review, we will discuss the role of adenosine and its receptors in wound healing, fibrosis, and scarring.

Figure 1.

Formation of adenosine from adenine nucleotides

Adenosine is formed both intracellularly and extracellularly from adenine nucleotides, which are sequentially dephosphorylated to adenosine. Intracellular adenosine may be transported into the extracellular space via facilitated transport, and extracellular adenosine is also taken up by cells through the same transporter, equilibrative nucleoside transporter 1 (ENT1). Two cell surface molecules, CD39 and CD73 (nucleoside triphosphate phosphohydrolase and ecto-5′-nucleotidase, respectively), catalyze the dephosphorylation of adenine nucleotides to adenosine in the extracellular space.

Adenosine in wound healing

Inflammation

The first step in wound healing involves the inflammatory response. Neutrophils, mast cells, monocytes/macrophages, and basophils all play a role in eliminating debris at injured sites, preventing infection of healing tissue and secreting factors that promote recruitment of new blood vessels and restoration of injured tissue. Adenosine, acting at its receptors, promotes the transition from a purely inflammatory role to promotion of tissue restoration. Since the first demonstration that adenosine suppresses inflammatory neutrophil functions in 1983 [1], it has been clear that adenosine, acting primarily at A_2A receptors, diminishes the inflammatory functions of both blood-borne and tissue inflammatory cells and even cells of the adaptive immune response (reviewed in [2]). More recent studies demonstrate that adenosine promotes macrophage differentiation into M2-type macrophages [3-5], which help to promote wound healing by releasing factors such as vascular endothelial growth factor (VEGF) that stimulate restoration of tissue at sites of injury (Figure 2).

Figure 2.

The role of adenosine A_2A and A_2B receptors in wound healing and inflammation

Adenosine in the extracellular space binds to either its A_2A or A_2B receptor, activating the G proteins Gq and Gs to mediate the effects shown. IL, interleukin; NK cell, natural killer cell.

Adenosine and fibrosis

Peritoneal fibrosis

A common complication of abdominal surgery or peritoneal dialysis is peritoneal fibrosis. Although peritoneal fibrosis is usually of little consequence, in some patients, peritoneal fibrosis can lead to bowel obstruction or other problems, so it is encouraging that recent studies in two different animal models of peritoneal fibrosis demonstrate that adenosine A_2A receptor blockade diminishes peritoneal fibrosis and adhesions [41].

Cardiac fibrosis

Dubey and colleagues [43] have reported that adenosine A_2B receptor activation inhibits cardiac fibroblast production of collagen in vitro. In agreement with these original findings, Wakeno and colleagues [44] have reported that adenosine A_2B receptor stimulation diminishes fibrosis and remodeling of the myocardium after infarction.

Conclusion

Adenosine, a nucleoside that is generated in the extracellular space from adenine nucleotides released at inflamed and hypoxic sites or as a result of metabolic stresses in some tissues and organs, stimulates wound healing, angiogenesis and, in some tissues, under some circumstances, fibrosis. A number of studies demonstrate that stimulated adenosine receptors play different roles in the pathogenesis of fibrosis depending on the tissue. Adenosine A_2B receptors in the heart inhibit fibrosis, whereas these same receptors promote fibrosis in the lungs. In contrast, in the skin, liver, and lungs, adenosine A_2A and A_2B receptors both mediate an increase in fibrosis. It is also striking that different adenosine receptors appear to play a dominant role in fibrosis in different organs; adenosine A_2A receptors are the dominant receptors in the skin, peritoneum, and liver but A_2B receptors are responsible for pulmonary fibrosis. Adenosine blockade at these receptors provides novel targets for new therapies in these difficult clinical settings.