A formation PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27484364 remain unknown, the occurrence of these episodes cannot be predicted in

A formation PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27484364 remain unknown, the occurrence of these episodes cannot be predicted in advance. Although much progress has been made during recent years in exploring the pathophysiology of the disease, research has largely focused on the role of the different plasma enzyme systems [3, 6]. Previously, a number of case studies reported the elevation of white blood cell (WBC) count and neutrophil granulocyte counts (NGC) during edematous attacks [7?0]. Some authors attributed this to hemoconcentration from the extravasation of plasma during the edematous episode [7, 8]. In 2010, our team confirmed these reports in a study conducted on 18 HAE patients: we found increased WBC count and NGC during edematous episodes. Further, we showed that the increase of NGC during the attack was greater than could be explained by hemoconcentration [11]. Notwithstanding these findings, the possible activation of NGs in HAE attacks has not yet been investigated. This is all the more strange, since NGs are known to have the potential to exert multiple influences on the kallikrein-kinin system. Neutrophil elastase (NE) eleased from activated NGs- can cleave and inactivate C1-INH [12]. This may contribute to the dysregulationof plasma enzyme systems and hence, to edema formation, as C1-inhibitor is the most potent regulator of the kallikrein-kinin system, by controlling the activity of kallikrein and of activated factor XII [2]. The activation of NGs may lead to the formation of neutrophil extracellular traps (NETs), which are filamentous structures of DNA and CEP-37440 web histones containing granular enzymes [NE and myeloperoxidase PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/25746230 (MPO), primarily] along with antimicrobial peptides [defensins, and pentraxin 3 (PTX3)] [13, 14]. NETs can provide a negatively charged surface suitable for the activation of the kallikrein-kinin and of the complement systems [15, 16]. On the other hand, the kallikrein-kinin system can be activated also on the surface of neutrophils [17] (Fig. 1). A variety of factors related to the activation of NGs have been identified [18?0], and all these might have their role in the pathomechanism of edema formation. The objectives of our study were as follows: 1. To confirm the previously described increase of NGC in a larger patient population, by analyzing peripheral blood samples obtained from the same C1-INH-HAE patients during symptomatic and symptom-free periods. 2. To investigate the possible activation of NGs during edematous episodes, by determining the levels of theFig. 1 Activation of neutrophil granulocytes and the kallikrein-kinin system. During neutrophil activation triggered by different substances, the released neutrophil elastase could cleave and inactivate C1-INH [12]. Besides, activated neutrophils can release neutrophil extracellular traps, and both processes may contribute to bradykinin release [13, 15]. On the other hand, high molecular weight kininogen and factor XII can attach directly to the surface of NGs. Prekallikrein, by contrast, binds to the cell membrane indirectly, through its docking protein, high molecular weight kininogen, which could create the conditions for the release of kinins (bradykinin and kallidin) through the activation of the cell-bound kallikrein-kinin system. This would be manifested by the factor XII-mediated activation of prekallikrein on one hand, and/or by the release of neutrophil-borne, active tissue kallikrein on the other [17]. [Abbreviations: IL = interleukin, TNF- = tumor necrosis factor-, LPS = lipo.