• Responsabile: dott.ssa Fleur Bossi

Background and Significance
Angioedema (AE) is a condition characterized by significant localized swelling of deeper layers of the skin or submucosal tissues that affects at least 20% of the population. AE is due to increased vascular permeability, leading to massive dermal and subcutaneous edema, becoming particularly life threatening if it occurs in the upper respiratory tract. The hereditary form of AE is an autosomal dominant disorder due to a decreased serum level of C1 inhibitor (C1-INH) or to a secretion of a non functional protein. The acquired form of AE is associated with the high consumption of C1-INH or to the presence of autoantibodies or induced by treatment with Angiotensin Converting Enzyme (ACE) inhibitors. The mediator that seems to be the main responsible for edema formation is bradykinin (BK), but the real contribution of other factors such as
complement components or peptides derived from BK catabolism (e.g. des-Arg9-BK) or from renin-angiotensin-aldosterone system remained to be defined. Furthermore AE episodes are localized at particular vascular sites and the mechanisms that maintained confined the edema has not been yet understood.
In spite of a lifelong stable C1-INH deficiency or of a continuous ACE inhibitor treatment, patients with these conditions are only seldom symptomatic, with huge variation in frequency and severity of symptoms and the mechanisms responsible for such variability is completely unexplained and the therapeutic tools are still not completely satisfying.
Specific aims
Aim 1: To identify the mediators responsible for increased vascular permeability in AE patients analyzing the role of kinins, of the soluble terminal complement complex and of renin-angiotensin-aldosterone system in inducing endothelial leakage.
Aim 2: To investigate the factors that maintain the event localized to a specific vascular site studying the tissue distribution of gC1q and bradykinin receptors and the stimuli that induce their membrane expression.
Aim 3: To analyse the enzymatic systems that promote AE episodes.
Available evidence suggests that the nonapeptide bradykinin (BK) may be largely responsible for the vascular permeability seen in acute attacks of AE but recent data collected in our laboratory indicate that other molecules could be also involved. For this reason we will analyze a large series of patients representing different clinical variants and different phases of the disease (spontaneous remission, attack, drug-induced remission) in order to better identify the factors responsible for the edema. In particular will be investigated the role of des-Arg9-BK and the potentiating effect of BK by angiotensin 1-7. Furthermore, since gC1qR has been shown to be a major site for the assembly and activation of the kinin system and the kinins released bind in turn to specific B1 and B2 receptors, and the edema developed during acute attacks is confined to particular vascular sites, we will analyse the different receptor expression between edematous and normal tissues. Our hypothesis is that blockade of both BK receptors and blockade of gC1qR can attenuate the vascular permeability and prevent the generation of BK. Since des-Arg9-BK is produced from BK by carboxypeptidase M along cell surface, we hypothesize that the blockade of the enzyme may also reduce the vascular leakage being a new potential target. The aim of the proposal is to thoroughly identify the mechanisms leading to the enhanced vascular permeability in clinical settings of AE by focusing not only on C1-INH deficiency as a primary disease model but also on ACE-inhibitor related AE in order to identify new possible therapeutic tools.
Impact and Translational Implications
AE causes significant personal and occupational disability and exposes patients to the risk of death. Because the pathogenic mechanisms are not completely understood, progress in diagnosis and treatment has been very slow. The results obtained from these studies will elucidate the factors involved in the onset of vascular permeability during the acute attacks, and will provide us a sound rationale to design therapeutic approaches for the prevention and treatment of the disease.


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