title: Collagenase-3 induction in rat lung fibroblasts requires the combined effects of tumor necrosis factor-alpha and 12-lipoxygenase metabolites: a model of macrophage-induced, fibroblast-driven extracellular matrix remodeling during inflammatory lung injury.
abstract: The mechanisms responsible for the induction of matrix-degrading proteases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of extracellular matrix at sites of inflammation. We find a localized increase in the expression of the rat interstitial collagenase (MMP-13; collagenase-3) gene from fibroblastic cells directly adjacent to macrophages within silicotic rat lung granulomas. Conditioned medium from macrophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medium from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene expression. Tumor necrosis factor-alpha (TNF-alpha) alone did not induce interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulation of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-alpha and 12-lipoxygenase-derived arachidonic acid metabolites. The fibroblast response to this conditioned medium was dependent on de novo protein synthesis and involved the induction of nuclear activator protein-1 activity. These data reveal a novel requirement for macrophage-derived 12-lipoxygenase metabolites in lung fibroblast MMP induction and provide a mechanism for the induction of resident cell MMP gene expression during inflammatory lung processes.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA. mariani@biochem.wustl.edu
authors.forename: T J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: S
authors.initials: S
authors.lastname: Sandefur
authors.forename: J D
authors.initials: JD
authors.lastname: Roby
authors.forename: R A
authors.initials: RA
authors.lastname: Pierce
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D017077:Culture Media, Conditioned; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000201:enzymology*; D015870:Gene Expression; D007700:Kinetics; D008168:Lung / Q000276:immunology; D008171:Lung Diseases / Q000201:enzymology; D055370:Lung Injury; D008264:Macrophages / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D012829:Silicosis / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat