Pathological overproduction: the bad side of adenosine

Abstract

Adenosine is an endogenous ubiquitous purine nucleoside, which is increased by hypoxia, ischaemia and tissue damage and mediates a number of physiopathological effects by interacting with four GPCRs, identified as A₁ , A_2A , A_2B and A₃ . Physiological and acutely increased adenosine is mostly associated with beneficial effects that include vasodilatation and a decrease in inflammation. In contrast, chronic overproduction of adenosine occurs in important pathological states, where long-lasting increases in the nucleoside levels are responsible for the bad side of adenosine associated with chronic inflammation, fibrosis and organ damage. In this review, we describe and critically discuss the pathological overproduction of adenosine and analyse when, where and how adenosine exerts its detrimental effects throughout the body.

Figure 1

Schematic representation of the adenosinergic system from adenosine formation and release to signalling and removal from the extracellular space. Alterations occurring during hypoxia are shown. 5′NT, 5′‐nucleotidase; ADA, adenosine deaminase; SAH, S‐adenosylhomocysteine.

Figure 2

Deleterious effects of adenosine mediated through A_2A and A_2B receptors expressed in different areas of the CNS. DRG, dorsal root ganglion.

Figure 3

Modulation of wound healing, angiogenesis and fibrosis by A_2B and A₃ receptors in inflammatory cells.

Figure 4

Deleterious effects of adenosine mediated through A_2B and A₃ receptors expressed in the lung and kidney. AAM, alternatively activated macrophages; HS, high salt; UNX, uninephrectomy.

Figure 5

Deleterious effects of adenosine mediated through A_2B and A₃ receptors in diabetes. α‐SMA, α‐smooth muscle actin.

Figure 6

Deleterious effects of adenosine mediated through A_2A and A_2B receptors in cancer.