Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene Dq (LTD4) is co-mitogenic with insulin-like growth f actors (IGFs) in airway smooth-muscle (ASM) cells in vitro. This synergisti c effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-pro duced ICF binding proteins (IGFBPs), which are cell growth-inhibitory prote ins. We also identified this IGFBP protease to be the matrix metalloprotein ase-1 (MMP-1), and showed that this enzyme had a significant role in modula ting IGF action in ASM cells. In the present study, we tested the hypothesi s that ASM hyperplasia in vivo involves induction of MMP-1 leading to IGFBP proteolysis. We detected the presence of MMP-1 and measured its levels in human airway tissue sections prepared from nonasthmatic and asthmatic subje cts. Six nonasthmatic and six asthmatic airway tissue samples were analyzed for immunoreactive MMP-1 through an immunohistochemical detection method. Both the bronchial and tracheal smooth-muscle cells from different regions of the same sample were examined and documented. The immunostaining for MMP -1 was significantly elevated in both the bronchial and tracheal smooth-mus cle cells of the airway sections from asthmatic samples relative to that of the nonasthmatic samples. The differences in levels of MMP-1, IGFBP-2, IGF BP-3, and IGFBP proteolytic activity were quantified using densitometric an alyses of the ASM tissue extracts that were separated on sodium dodecyl sul fate-polyacrylamide gel electrophoresis. The MMP-1 levels in the asthmatic airway tissue extracts were 12-fold higher than those found in control samp les. In addition, IGFBP-2 and IGFBP-3, which we have previously demonstrate d to be proteolytic substrates of MMP-1, were found to be cleaved in asthma tic airway tissue extracts. Furthermore, the asthmatic airway extracts cont ained IGFBP proteolytic activity that was shown by immunodepletion studies to be due to MMP-1. These observations demonstrate that MMP-1 may play a si gnificant role in inducing ASM hyperplasia and airway obstruction in asthma by modulating the IGF axis.