Abstract
The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.
Highlights
Angioedema (AE) is usually defined as a recurrent, self-limiting edema localized and lasting for a few hours or until five days
In this review we aimed to summarize the recent advances in the AE pathogenesis, focusing on the role of the plasminogen activation (PA) system
The plasminogen activation (PA) system is a well-characterized proteolytic system composed of the zymogen plasminogen, the active protease plasmin, the urokinase-type and tissue-type plasminogen activators, a plasma membrane-associated receptor, and two inhibitors, plasminogen activator inhibitor 1 and 2
Summary
Angioedema (AE) is usually defined as a recurrent, self-limiting edema localized and lasting for a few hours or until five days. AE attack can result from bradykinin overproduction and/or from inflammatory mediators released by mast cells’ degranulation, primarily histamine. According to the European Academy of Allergy and Clinical Immunology (EAACI) [6], five different forms of hereditary angioedema (HAE) have been identified: HAE-1, due to C1 inhibitor (C1-INH) deficiency, characterized by low antigenic and functional C1-INH levels; HAE-2, due to C1-INH dysfunction, characterized by normal (or elevated) antigenic but low functional C1-INH levels [7,8]; HAE-FXII, characterized by mutation in the coagulation factor 12 (F12) gene [9]; HAE-ANGPT1 with mutation in the angiopoietin-1 gene [10]; HAE-PLG with mutation in the plasminogen gene [11]. Ariano A. et al identified a new form of HAE associated with a myoferlin mutation [12]. We discuss the potential of the PA system as a new molecular target for AE therapy development
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