Analysis of the molecular mechanisms of C1-inhibitor deficiency induced angioedema

Purpose: Angioedema (AE) due to inherited or acquired deficiencies of C1 inhibitor (C1-INH) is characterized by localized swelling of deeper layers of the skin or submucosal tissues, becoming particularly life threatening if it occurs in the upper respiratory tract. C1-INH regulates the release of bradykinin which can enhance permeability of post-capillary venules interacting with its receptors. The drugs currently used are more symptomatic than curative, so we sought to identify the molecular mechanisms responsible for the induction of vascular permeability. Methods: We used a transwell in vitro model with a filter covered by primary human endothelial cells (EC), in the upper chamber we add the fluorescent-BSA and the stimuli and the BSA leaked into the lower chamber was evaluated using a Fluorescence reader. Results: EC were incubated with plasma collected from patients during attack (APL) and the presence of C1-INH in the majority of the patients was able to block the permeability. To mimic the in vivo situation we stimulated the EC with the APL for 30 min and then the SN was collected and used to stimulate the ECs in the transwell model. In that case the inhibition of the leakage by C1-INH was not seen in all the patients. This observation was further confirmed by using the plasma collected from 1 patient before and 1 h after the clinical treatment with C1-INH, indeed there is no difference in the EC leakage induced by the plasma before and after the treatment. Discussions: The inhibition of endothelial leakage induced by APL stimulation by C1-INH indicates the involvement of that molecule in controlling the onset of AE attacks, although the inability of C1-INH to completely block the permeabilizing effect of the SN indicates that after the activation of the cells there are other molecules involved. Conclusion: Since the clinical treatment of AE can be done with different drugs besides C1-INH we have to analyze the most appropriate therapeutic approach.