Background: Adenosine is an endogenous nucleoside known to promote the synthesis of matrix proteins in the skin. Fibrogenesis in the skin is enhanced in a murine model of high tissue adenosine. Further, acting through one of its cell surface receptors, the A2A receptor, adenosine promotes normal and diabetic wound healing. Thus, adenosine is a known stimulant for fibrous matrix production in the dermis and in wounds. This chapter examines the effects of loss of adenosine on fibrogenesis in the liver. Ecto-50-nucleotidase (CD73) is a cell surface enzyme that catalyzes the dephosphorylation of AMP to adenosine extracellularly. CD73 deficiency in a murine model effectively reduces adenosine levels in the blood and tissues, providing a mechanism to study the effects of loss of adenosine directly. Previous studies have demonstrated a potent pro-fibrotic effect of adenosine in the lung, liver, and skin. The Problem: Does a relative lack of adenosine protect against the development of hepatic fibrosis in toxin-induced murine models? Is the adenosine that is responsible for stimulating tissue fibrous matrix production generated extracellularly? What are the mechanisms by which adenosine exerts its fibrogenic effects?

Basic/Clinical Science Advances: Adenosine is a key pro-fibrotic mediator that is generated extracellularly. Loss of the cell surface enzyme CD73 effectively reduces adenosine levels in the liver. The fibrogenic effects of adenosine are mediated through the induction of tissue matrix protein synthesis, by suppression of tissue matrix breakdown, and by indirect effects on other profibrotic cytokines and growth factors. Clinical Care Relevance: The ability of adenosine to augment tissue fibrous matrix production provides a novel therapeutic target to promote wound healing.