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\r\ninvolved in the breakdown and remodelling of the extracellular randomatrix\r\n(ECM) under a variety of physiological and pathological conditions.\r\nIncreasing evidence shows that MMP-9 may be up-regulated\r\nby the exposition to cigarette smoke and that lycopene may counteract\r\nseveral signal pathways affected by cigarette smoke exposure.\r\nHowever, at the moment, it is unknown if this carotenoid may inhibit\r\ncigarette smoke-induced MMP-9 expression. Presently, we examined\r\nthe inhibitory mechanism of lycopene on MMP-9 induction in\r\ncultured human macrophages (THP-1 cells), in isolated rat alveolar\r\nmacrophages (AMs) and in cultured RAT-1 fibroblasts, all cellular\r\nsources of MMP-9, exposed to cigarette smoke extract (CSE). CSE\r\ninduced a marked increase in MMP-9 expression in cultured as well\r\nas in isolated cells. Lycopene pre-treatment (0.5–2 μM) reduced CSEmediated\r\nMMP-9 induction in a dose- and time-dependent manner.\r\nLycopene attenuated CSE-mediated activation of Ras, enhancing the\r\nlevels of this protein in the cytosolic fraction. Moreover, lycopene\r\ninhibited CSE-induced ERK1/2 and NF-κB activation in a dosedependent\r\nmanner. Lycopene-mediated inhibition of MMP-9 was\r\nreversed by mevalonate and associated with a reduced expression\r\nof 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.\r\nTaken together, these results suggest that lycopene may inhibit CSEmediated\r\nMMP-9 induction, primarily by blocking prenylation of Ras\r\nin a signaling pathway, in which MEK1/2-ERK1/2 and NF-κB are\r\ninvolved.