Adenosine is an extracellular nucleoside that is elevated in tissues during hypoxia and ischemia reperfusion, and has been implicated in asthma and other lung disorders. There, adenosine is considered an important modulator of physiological functions and inflammation, but its effects on matrix expression and turnover during tissue remodeling are unknown. We examined the effects of adenosine on lung epithelial cells with particular attention to the expression of fibronectin, a matrix glycoprotein highly expressed in injured tissues that has been implicated in wound healing. In A549 lung epithelial cells, we found that adenosine induced the expression of fibronectin mRNA and protein in a dose- and time-dependent manner, and found that the stimulatory effect of adenosine was inhibited by specific adenosine receptor antagonists. Adenosine stimulation was associated with increased levels of intracellular cyclic AMP, and with phosphorylation and DNA binding of the cyclic AMP response element binding protein (CREB), known for its ability to stimulate fibronectin gene transcription. To confirm the latter, A549s were transfected with a DNA construct containing the human fibronectin promoter connected to a luciferase reporter gene. Adenosine stimulated the transcription of the gene, and this effect was blocked by inhibitors of protein kinase activation. Finally, we tested primary lung fibroblasts and primary alveolar epithelial type II cells and found increased fibronectin expression in response to adenosine. Overall, our observations suggest that adenosine might modulate tissue remodeling by stimulating fibronectin expression in lung epithelial cells through induction of purinergic receptor-mediated signals that target CREB phosphorylation and stimulate fibronectin gene transcription.