Breakdown of the BBB has been related to the presence of various MMPs. MMPs are an endogenous family of zinc-dependent enzymes that are responsible for matrix remodeling. The extracellular matrix molecules, including type IV collagen, laminin, and fibronectin, constitute the basement membrane and help maintain the integrity of the BBB. Several types of MMPs have been shown to participate in the degradation of basal lamina and disruption of the BBB in the animal model, and their inhibition has been shown to be helpful in reducing the vasogenic edema in ICH (40,79).
Tissue inhibitor of metalloproteinases (TIMP), especially (TIMP-2), which is found in the brain parenchyma, can be administered in experimental ICH to decrease perihematoma edema by protecting the BBB (80). In humans, a high blood concentration of MMP-9 detected within the first 24 hr of ICH (81) was associated with early edema and edema progression in the subsequent days, whereas high MMP-3 concentration correlated with mortality and residual scar volume (82). MMP-9 concentration was also found to serve as a biologic marker for predicting ICH complications after thrombolytic therapy in human ischemic stroke (83) and hematoma expansion (23) , which would suggest that MMPs are predisposing factors for hemorrhage. Interestingly, activation of MMPs was observed in heart transplant recipients when donors died following spontaneous ICH. These heart transplant recipients demonstrated upregulation of MMP-2 and MMP-9, which was associated with cardiac remodeling and subsequent development of coronary vasculopathy (84 ).
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