MMPs are a family of zinc dependent proteases that were initially identified in the involuting tail of tadpoles by their ability to degrade collagen.8
MMPs can be broadly classified on the basis of substrate specificity into collagenases (MMP‐1, ‐8 and ‐13), gelatinases (MMP‐2 and ‐9), stromelysins (MMP‐3, ‐10, ‐11), elastases (MMP‐7 and ‐12), and membrane type MMPs (MT‐MMPs, MMP‐14, ‐15, ‐16 and ‐17) which are surface anchored. MMP‐1 (interstitial collagenase), MMP‐8 (neutrophil collagenase), MMP‐13 (collagenase 3), and MMP‐14 (MT1‐MMP) can cleave the triple helix of native type I collagen,7
the primary architectural collagen of the lung.3
Elastolytic MMPs include MMP‐2 (gelatinase A), MMP‐7 (matrilysin), MMP‐9 (gelatinase B), and MMP‐12 (macrophage metalloelastase).
Since MMPs may cause significant host damage, they are tightly regulated. Firstly, they are rarely stored but require gene transcription before secretion, the exception being neutrophil MMP‐8 and ‐9. Secondly, they are either secreted as pro‐enzymes that require proteolytic cleavage or, in the case of MT‐MMPs, activated intracellularly by pro‐protein convertases such as furin. This processing exposes the catalytic cleft, a mechanism known as the cysteine switch.9
Thirdly, specific inhibitors of MMPs—the tissue inhibitors of metalloproteinases (TIMPs)—are secreted which bind MMPs in a 1:1 manner to prevent enzymatic activity.10
The balance of MMPs to TIMPs therefore determines matrix turnover, where either an excess of MMPs or a deficit of TIMPs may result in excess ECM degradation. Finally, MMPs can be compartmentalised in close proximity to the cell.
The majority of MMPs are not expressed in normal healthy tissues but are expressed in diseased tissues that are inflamed or undergoing repair and remodelling.11
MMP expression may be upregulated by exogenous stimuli, cytokines and cell‐cell contact. Conversely, cytokines such as interferon (IFN)‐γ and interleukins (IL)‐4 and ‐10 may downregulate MMP expression. Both inflammatory and stromal cells can express MMPs, although the profile is both cell and stimulus specific. For example, macrophages express a wider profile and greater quantities of MMPs than monocytes.12
Pulmonary epithelial cells may also be a significant source of MMPs as they express MMP‐1, ‐2, ‐7 and ‐9.13,14,15
Intracellularly, MMP secretion is primarily regulated by the prostaglandin (PG) and mitogen activated protein kinase (MAPK) signal transduction pathways.15,16,17
The complexity of proteinase interactions is illustrated by the manner in which MMP‐9 deficiency prevents neutrophil elastase induced immunopathology. In a model of autoimmune skin disease, MMP‐9 deficient mice were found to be resistant to blister formation.18
However, a direct role for MMP‐9 was not identified. Instead, MMP‐9 is responsible for cleaving the serpin α1
‐proteinase inhibitor which then results in uninhibited neutrophil elastase activity. Multiple proteases may therefore be involved in a cascade, with a single one causing the final pathology but upstream enzymes being equally critical to the process.