COLLAGENASE-3 INDUCTION IN RAT LUNG FIBROBLASTS REQUIRES THE COMBINEDEFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA AND 12-LIPOXYGENASE METABOLITES - A MODEL OF MACROPHAGE-INDUCED, FIBROBLAST-DRIVEN EXTRACELLULAR-MATRIX REMODELING DURING INFLAMMATORY LUNG INJURY

The mechanisms responsible for the induction of matrix-degrading prote ases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of ex tracellular matrix at sites of inflammation. We find a localized incre ase in the expression of the rat interstitial collagenase (MMP-13; col lagenase-3) gene from fibroblastic cells directly adjacent to macropha ges within silicotic rat lung granulomas. Conditioned medium from macr ophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medi um from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene e xpression. Tumor necrosis factor-alpha (TNF-alpha) alone did not induc e interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulatio n of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-alpha and 12-lipoxygenase-de rived arachidonic acid metabolites. The fibroblast response to this co nditioned medium was dependent on de novo protein synthesis and involv ed the induction of nuclear activator protein-1 activity. These data r eveal a novel requirement for macrophage-derived 12-lipoxygenase metab olites in lung fibroblast MMP induction and provide a mechanism for th e induction of resident cell MMP gene expression during inflammatory l ung processes.