Asthma is characterized by an increased production of eosinophil-active C-C chemokines by the airway epithelium. Recent studies have identified the presence of important quantities of labile zinc in the conducting airways. We hypothesized that modulation of this labile zinc could influence the production of pro-inflammatory chemokines in respiratory epithelial cells. The zinc chelator TPEN (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine) and the heavy metal chelator DMPS (2,3-Dimercapto-1-propanesulfonic acid) were used to reduce the labile zinc content of A549, BEAS-2B and HFL-1 cells. Northern blot analysis and RPAs were used to study the effects of the zinc chelators on mRNA expression. DMPS and TPEN specifically inhibited the production of eotaxin, RANTES and MCP-1 in TNF--stimulated respiratory epithelial cells and fibroblasts through labile zinc chelation. The inhibitory effects of DMPS and TPEN were associated with the decreased binding of the zinc-finger transcription factor GATA-1 whereas no change in NF-B activation was observed. Taken together these results demonstrate that modulation of the labile pool of zinc can regulate gene expression and protein synthesis of C-C chemokines in lung epithelial cells and fibroblasts.