ACT,a pathophysiological inhibitor of MMP-9 activation

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DESCRIPTION (provided by applicant): Abnormal wound healing is a major health problem in United Sates with the increasing of aging society. Our long term goal is to elucidate the function and mechanism of matrix metalloproteinases in tissue repair. Remodeling of extracellular matrix (ECM) is essential in tissue repair and carried out by specific proteinases and inhibitors. Interruption of ECM remodeling by either insufficient or excessive degradation is linked to abnormal healing such as hypertrophic scar and chronic wounds. Massive activation of matrix metalloproteinase-9 (MMP-9), by cleavage of the pro-domain, has been well documented in chronic wound and other degenerative diseases such as cancer metastasis. We previously characterized the proMMP-9 activator as a tissue bound chymotrypsin-like proteinase. Recent study showed the presence of inhibitory factor(s) in acute wound fluid, which prevents conversion of proMMP-9 into the active 82-kDa enzyme. Simultaneously, we identified alpha 1-antichymotrypsin (alpha-ACT), an acute phase factor, as a potent inhibitor for proMMP-9 activation. Conversely, in chronic wounds alpha-ACT is degraded, non-functional and loses its inhibition of proMMP-9 conversion. In addition to liver hepatocytes we also identified skin keratinocytes as a previously unrecognized source of alpha-ACT. In this proposal we will address three specific aims: 1) to demonstrate the role of alpha-ACT as a pathophysiological inhibitor in wound healing; 2) to define the mechanism by which alpha-ACT inhibits proMMP-9 activation; 3) to investigate the mechanism of cytokine-regulated expression of alpha-ACT by skin keratinocytes and the wound tissue. Understanding the function, structure and regulation of the inhibitor can provide information for future application in developing of therapy for abnormal wounds and cancer metastasis.