Collagenase-3 Induction in Rat Lung Fibroblasts Requires the Combined Effects of Tumor Necrosis Factor-α 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.

Comparative study of the properties of tendinocytes derived from three different sites in the equine superficial digital flexor tendon

“…Therefore, TNFα has a stimulatory effect on production of proMMP-13 in cultured tendinocytes. Proinflammatory cytokines, such as IL-1β and TNFα, stimulate synthesis of MMPs in various types of cells (12,18,24,42). In a normal tendon, restricted MMP-13 expression was observed in some fibroblastic cells and vascular component in the endotenon, suggesting the participation of MMP-13 in maintenance of homeostasis in matrix turnover in a tendon.…”

Macrophage Phenotype and Renal Fibrosis in Obstructive Nephropathy

“…Indeed, M2 macrophages produce large amounts of TGF-β [18] and can induce myofibroblast proliferation [19]. In contrast, M1 macrophages produce MMPs [19, 20] and can also induce myofibroblasts to produce MMPs [21] that promotes ECM degradation and facilitates the resolution of fibrosis. Furthermore, MMPs may contribute to the resolution of fibrosis by stimulating myofibroblast apoptosis [22].…”

Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair

“…Myofibroblasts also have the capacity to express MMPs and tissue inhibitors of metalloproteinase (TIMPs), through which they regulate degradation of matrix components (9). The precise role of macrophages at the site of injury is unclear (10,11), but they are known from in vitro experiments to generate a diverse array of agents that regulate the degradation of matrix (7,10,12,13).…”