Lycopene Influences Tissue Remodelling Through Regulation of MMP-9 in Macrophages and Fibroblasts Exposed to Cigarette Smoke

Matrix metalloproteinase-9 (MMP-9) is a neutral proteinase involved in the breakdown and remodelling of the extracellular randomatrix (ECM) under a variety of physiological and pathological conditions. Increasing evidence shows that MMP-9 may be up-regulated by the exposition to cigarette smoke and that lycopene may counteract several signal pathways affected by cigarette smoke exposure. However, at the moment, it is unknown if this carotenoid may inhibit cigarette smoke-induced MMP-9 expression. Presently, we examined the inhibitory mechanism of lycopene on MMP-9 induction in cultured human macrophages (THP-1 cells), in isolated rat alveolar macrophages (AMs) and in cultured RAT-1 fibroblasts, all cellular sources of MMP-9, exposed to cigarette smoke extract (CSE). CSE induced a marked increase in MMP-9 expression in cultured as well as in isolated cells. Lycopene pre-treatment (0.5–2 μM) reduced CSEmediated MMP-9 induction in a dose- and time-dependent manner. Lycopene attenuated CSE-mediated activation of Ras, enhancing the levels of this protein in the cytosolic fraction. Moreover, lycopene inhibited CSE-induced ERK1/2 and NF-κB activation in a dosedependent manner. Lycopene-mediated inhibition of MMP-9 was reversed by mevalonate and associated with a reduced expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Taken together, these results suggest that lycopene may inhibit CSEmediated MMP-9 induction, primarily by blocking prenylation of Ras in a signaling pathway, in which MEK1/2-ERK1/2 and NF-κB are involved.