**3. Activation of metalloproteinases**

Metalloproteinases are encoded as inactive proenzymes, zymogens. They undergo proteolytic activation. This process can take place either intracellulary or extracellulary. One third of MMPs are activated by intracellular serin protease, furin. This process takes place in trans-Golgi network. A number of MMPs has a cleavage site for other metalloproteinases. MMP-3 activates proMMP-1 and pro-MMP-7. Some metalloproteinases have been described to be activated by kallikrein or plasmin.

*In vivo* studies indicate that reactive oxygen species (ROS) generated by neutrophils can both activate and subsequently inactivate MMPs. Hypochlorus acid (HClO) generated by neutrophil myeloperoxidase and hydroxyl radicals can activate proMMP-1, proMMP-7 and proMMP-9, whereas peroxynitrate can activate proenzymes of MMP-1, MMP-2 and MMP-9. This process enables a control of burst of proteolytic activity within an inflammatory setting.

Like some other proteases, activity of MMPs is controlled also by two other mechanisms, regulation of gene expression and specific inhibitors. MMP-2 is constitutively expressed and regulation of its activity occurs by either activation or inhibition. Expression of a number of metalloproteinases is up-regulated during various pathological conditions. Among them inflammation is the most studied setting. MMPs are inhibited by α-2 macroglobulin and tissue inhibitors of metalloproteinases (TIMPs). There are four TIMPs. Their secretion is also regulated and represents another point in a network of control of the activity of metalloproteinases. TIMP-3 is primarily bond to ECM and allows a regulation of MMPs' activity in the very site of their action. The network of the control of the activity of metalloproteinases is complex and very precise. Sometimes TIMP interacts with proMMP and inactivate other MMP, e.g. a complex of TIMP-1 and proMMP-9 inactivates MMP-3.

Protection from MMP degradation represents the next step in this sophisticated network of diverse interactions. Neutrophil gelatinase-associated lipocalin (NGAL) bounds to MMP-9 protecting this metalloproteinase from its degradation [1,2].
