Endogenous mediators within the inflammatory milieu play a critical role in directing the scope, duration and resolution of inflammation. High molecular weight extracellular matrix hyaluronan helps to maintain homeostasis. During inflammation, hyaluronan is broken down into fragments that induce chemokines and cytokines thereby augmenting the inflammatory response. Tissue derived adenosine, released during inflammation, inhibits inflammation via the anti-inflammatory A2a receptor. We demonstrate that adenosine modulates hyaluronan-induced gene expression via the A2a receptor. A2a receptor stimulation inhibits HA fragment-induced pro-fibrotic genes TNF-, KC, MIP-2 and MIP-1 while simultaneously synergizing with hyaluronan fragments to up-regulate the TH1 cytokine IL-12. Interestingly, A2a receptor stimulation mediates these affects via the novel cAMP-activated guanine nucleotide exchange factor EPAC. Additionally, A2a receptor null mice are more susceptible to bleomycin-induced lung injury consistent with a role for endogenous adenosine in inhibiting the inflammation that may lead to fibrosis. Indeed, the bleomycin treated A2a receptor null mice demonstrate increased lung inflammation, hyaluronan accumulation and histologic damage. Overall, our data elucidate the opposing roles of tissue derived hyaluronan fragments and adenosine in regulating non-infectious lung inflammation and support the pursuit of A2a receptor agonists as a means of pharmacologically inhibiting inflammation that may lead to fibrosis.