MMPs, Matrix metalloproteases

ROS, reactive oxygen species AHR, airway hyperresponsiveness MMP, matrix metalloprotease. Correlates with cough and chronic bronchitis. bNumber increases with disease severity. 

Fig. 5.4 Angiotensin II mediates multiple physiological and pathophysiological responses in the vessel wall.The vessel wall undergoes numerous structural and functional changes mediated by the. A l l R, all of which are considered proatherogenic once physiological thresholds are crossed. See text for details. Ang II, angiotensin II EC, endothelial cell MC, monocyte/macrophage MMP, matrix metalloprotease NO, nitric oxide PAI-1, plasminogen activator inhibitor-1. ECM, extracellular matrix ROS, reactive oxygen species.

Cleaved Peptide [ MMP Matrix metalloprotease Figure 20,7 MMP-responsive drug release system. 

One intensively investigated feature of the inflammatory process in COPD is the release of proteases from neutrophils and monocytic cells that destroy elastin and other components of the interstitial matrix (Table 1). The best studied protease is neutrophil elastase. Independent of its elastolytic activity, neutrophil elastase is a potent secretagogue. More recently matrix metalloproteases (MMP) have received increasing attention, in particular MMP 12 (macrophages elastase). To which extent and how exactly these proteases become activated is not clear at present. 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

The matrix metalloprotease (MMP) family of zinc hydrolases are thought to play important roles in extracellular tissue remodeling in angiogenesis and other normal physiological processes, in some inflammatory processes and in metastatic processes in cancer. Like the zinc carboxypeptidases, the MMPs also utilize a zinc-coordinated water molecule to initiate attack on the scissile amide bond of protein substrates. These enzymes are synthesized by the ribosome in a latent form composed of a catalytic domain and an N-terminal extension, referred to as the prodomain the latent, or inactive form of the enzyme is referred to as a zymogen or... 

T cell activation in the lamina propria is associated with epithelial cell shedding, leading to loss of villi. It has been postulated that this is mediated by increased production of matrix metalloproteases (MMP), which, by degrading the lamina propria matrix, represent a major pathway by which T cells cause injury in the gut (Pender et al., 1997). Production of MMPs also facilitates movement of cells out of the vasculature into sites of inflammation and contributes substantially to the degradation of connective tissue during inflammatory disease (Stetler-Stevenson, 1996). Furthermore, MMPs are required for the release of soluble TNF-a from its membrane... 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

Yang Z, Ma M, Xu B (2009) Using matrix metalloprotease-9 (MMP-9) to trigger supramolecular hydrogelation. Soft Matter 5 2546-2548... 

Metalloproteases include carboxypeptidase [1, 29, 30], ACE (a dipeptidyl carboxypeptidase) [13, 31] and a variety of matrix metalloproteases (matrixins or MMPs) [1, 32, 33]. ACE catalyzes the formation of the vasoconstrictive hormone angiotensin II from angiotensin I, some ACE inhibitors being important anti-hypertensive drugs [13, 31]. 

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