Increased expression of tissue inhibitor of metalloproteinase-1 and loss of correlation with matrix metalloproteinase-9 by macrophages in asthma.Lab Invest. 1999 Jan; 79(1):39-47.LI
Alveolar macrophages (AMs) can mediate tissue destruction and repair by synthesizing matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) as well as inflammatory cytokines, which regulate their production. Imbalances between these enzymes and inhibitors may contribute to the tissue damage and remodeling seen in inflammatory diseases. In this study, we examined the role of AMs in chronic asthma. We have previously demonstrated an increased production of MMP-9 by AMs in untreated asthmatic patients as compared with healthy subjects, and in asthmatics treated with inhaled corticosteroids and patients with chronic bronchitis. We now report on the expression of TIMP-1, the inhibitor of MMP-9, and compare the levels and the regulation by cytokines of both MMP-9 and TIMP-1. Enzyme and inhibitor were measured using an enzyme immunoassay and immunoprecipitation. TIMP-1 steady-state mRNA levels were measured using the RNase protection assay. AMs from untreated asthmatics were found to produce more TIMP-1 both at protein and mRNA levels than AMs from other groups. The release of TIMP-1 and MMP-9 from individual AMs was significantly correlated in control populations and the molecules mainly complexed to each other, whereas this was not true for untreated asthmatics, indicating an imbalance between MMP-9 and TIMP-1 production. In the latter population, TIMP-1 release was inhibited by an anti-IL-6 antibody and MMP-9 release by anti-TNF-alpha, anti-IL-6, and anti-IL-1/beta antibodies. The imbalance of MMP-9 and TIMP-1 production, via the involvement of different cytokines, suggests that AMs may be involved in the abnormal repair observed in chronic asthma.