TIMP-1 in asthma

O ver the last few years there has been increasing interest in the matrix metalloproteinases (MMPs) in asthma. The MMPs are a family of over 20 zinc dependent endopeptidases with a range of substrate specificities. Although originally classified into gelatinases, stromolysins, collagenases, and matrilysins by their ability to cleave extracellular matrix components, it is now clear that MMPs have an increasing range of other functions. Of potential relevance to asthma is the release and activation of growth and angiogenic factors including transforming growth factor b (TGFb) and vascular endothelial growth factor (VEGF), apoptosis by release of Fas ligand, and activation of cell surface receptors—collectively resulting in effects on cell differentiation, survival, proliferation, and migration. MMP activity is tightly regulated at several levels. Gene transcription is enhanced by growth factors, cytokines and adhesion molecules and downregulated by TGFb and corticosteroids. MMPs are secreted as zymogens which require activation by proteolytic cleavage either at the cell surface or in solution by other proteases including MMPs. Once activated, natural inhibitors including tissue inhibitors of metalloproteinases (TIMPs) bind different MMPs with varying specificities in a 1:1 ratio to inhibit proteolytic activity. There are four TIMP proteins which, in addition to their antiprotease actions, also have other functions—with TIMP-1 modulating proliferation, apoptosis, and angiogenesis in various tumour cell types. 8