Chronic inflammation and eventual tissue fibrosis are characterized by an accumulation of inflammatory cells and mediators, and also by an increased turnover of the extracellular matrix (ECM). Breakdown of the ECM yields low molecular weight fragments of components such as hyaluronan (HA) that are now bioactive within the inflammatory milieu. We have previously demonstrated that these HA fragments stimulate macrophage production of known mediators of tissue injury and repair such as TNF-a, MlP-1a, IL-12, and IP-10. Recently, we have shown that the A2a receptor specific adenosine agonist CGS exerts profound inhibitory effects on HA-induced inflammatory mediators.
The aim of this proposal is to characterize the effect of adenosine on expression of pro-inflammatory genes induced in macrophages by HA fragments and the mechanism by which adenosine modulates these HA fragment-induced genes. We will also explore whether adenosine modulation of inflammatory genes will have an effect upon bleomycin-induced lung inflammation and fibrosis. We hypothesize that adenosine regulates HA-induced inflammatory genes via engagement of the A2a adeonsine receptor.
