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Background In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately. Objective The aim of this study was to study the effect of primary human AEC on the proliferation of fibroblasts obtained from healthy and fibrotic lungs in an interactive cell culture model. Results Conditioned medium (CM) from 14 out of 16 AEC lines significantly inhibited proliferation of normal human lung fibroblasts by 51.2±6.0%. The proliferation of fibroblasts derived from patients with lung fibrosis was equally inhibited by CM of AEC. The inhibitory effect of AEC-CM was completely reversed when fibroblasts were pre-incubated with 2.5 μm indomethacin. Furthermore, primary human AEC, but not fibroblasts, secrete TGF-β, and the inhibitory effect of the AEC-CM was blocked by neutralizing anti-TGF-β antibodies. Conclusion These results demonstrate that AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-β, which induces the prostaglandin E2 synthesis in fibroblasts. The data indicate that proliferative lung diseases may be treated using the epithelial cell as the target of medication. [ABSTRACT FROM AUTHOR]