Matrix metalloproteinases in lung repair.

The aims of this article are to discuss current concepts of the function of matrix metalloproteinases (MMPs), with an emphasis on identification of authentic substrates. Focusing on matrilysin (MMP-7), it is demonstrated how a single extracellular proteinase can regulate key and common functions of epithelial biology, namely defence against microorganisms , re-epithelialisation in response to injury and acute inflammation. Using findings from models of acute lung injury, the mechanism of matrilysin9s action in these processes , that is, the proteins it acts upon to facilitate specific biological processes is discussed. Despite their specialisation to serve distinct functions, the epithelium of different tissues respond similarly to injury and infection and regulate inflammation by equivalent mechanisms. By forming a barrier and releasing antimicrobial products, epithelia provide the first line of defence against invading pathogens. Following injury, epithelial cells initiate a programmed series of coordinated responses to restore tissue integrity. By their production of chemoattractants, adhesion molecules, and other proteins, epithelial cells recruit and confine inflammatory cells to sites of injury. Though seemingly divergent processes, the epithelial programmes regulating repair, defence and inflammation may have co-evolved, particularly with respect to the genes selectively induced. After all, injury provides an opportunity for infection, which can lead to injury; both events being proinflammatory. Hence, many of the epithelial products associated with any one of these events are likely common to all. Matrilysin (MMP-7), is an example of a protein that functions in defence, repair, and as shown here, inflammation. MMPs comprise a family of 23 (currently) related, yet distinct enzymes. MMPs are secreted or anchored to the cell surface [1, 2], thereby confining their catalytic activity to membrane proteins or proteins within the secretory pathway or extracellular space. As their name suggests, MMPs are thought to be responsible for the turnover and degradation of connective tissue proteins, a function that is likely performed by some family members. However, matrix degradation is neither the sole nor shared function of these enzymes. Several reports in recent years have demonstrated that various MMPs can activate a variety of nonmatrix proteins, including cytokines, chemokines, receptors and antimicrobial peptides [3]. Thus, MMPs should not be viewed solely as proteinases of matrix catalysis, but rather, as mentioned above, as extra-cellular processing enzymes involved in regulating cell-cell and cell-matrix signalling events. The use of genetically defined mice has allowed investigators to uncover specific and, at times, unexpected functions of MMPs. Of the …