All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) in human bronchoalveolar lavage cells

Background: The balance between proteinases and antiproteinases plays an im portant role in tissue destruction and remodelling. In chronic obstructive pulmonary disease (COPD) and emphysema, an imbalance between matrix metallo proteinases (MMPs) and inhibitors of tissue metalloproteinase (TIMPs) has b een reported, Alveolar macrophages are considered to be the main source of MMPs. We therefore have analyzed the effects of free and liposomal all tran s-retinoic acid (ATRA) on the expression of MMP-9 and TIMP-1 in bronchoalve olar lavage (BAL) cells from patients with COPD and patients with other lun g diseases. Material and Methods: BAL cells were incubated 1-3 day with either liposoma l or free ATRA. Supernatants were tested for MMP-9 and TIMP-1 protein in sp ecific ELISA systems; mRNA analysis was performed by semiquantitative RT-PC R and by quantitative LightCycler PCR. Results: We demonstrate that either liposomal or free ATRA selectively down -regulates MMP-9 and up-regulates TIMP-1. At the protein level, MMP-9 is de creased 3-fold and TIMP-1 is increased 3.5-fold compared to the base line w ith empty liposomes or untreated cells. The ratio of MMP-9 and its inhibito r TIMP-1, which may be crucial to the overall proteolytic potential decreas ed by factor 8. That this countercurrent effect of ATRA is not due to an al tered protein stability but to transcriptional regulation could be demonstr ated by RT-PCR. Quantitative LightCycler analysis revealed a 2.5-fold decre ase of MMP-9 mRNA and a 4.5 fold increase of TIMP-1 mRNA. Conclusions: These data suggest that ATRA treatment via its impact on the p roteinase/antiproteinase ratio may become a new therapeutic strategy for pa tients with inflammatory destructive lung diseases.