Activation Of Plasma Kallikrein-kinin System Research Articles

Tracing the plasma kallikrein-kinin system-activating component in the atmospheric particulate matter with different origins

Atmospheric particulate matter (PM) perturbs hematological homeostasis by targeting the plasma kallikrein-kinin system (KKS), causing a cascade of zymogen activation events. However, the causative components involved in PM-induced hematological effects are largely unknown. Herein, the standard reference materials (SRMs) of atmospheric PM, including emissions from the diesel (2975), urban (1648a), and bituminous coal (2693), were screened for their effects on plasma KKS activation, and the effective constituent contributing to PM-induced KKS activation was further explored by fraction isolation and chemical analysis. The effects of three SRMs on KKS activation followed the order of 2975 > 1648a > 2693, wherein the fractions of 2975 isolated by acetone and water, together with the insoluble particulate residues, exerted significant perturbations in the hematological homeostasis. The soot contents in the SRMs and corresponding isolated fractions matched well with their hematological effects, and the KKS activation could be dependent on the soot surface oxidation degree. This study, for the first time, uncovered the soot content in atmospheric PM with different origins contributed to the distinct effects on plasma KKS activation. The finding would be of utmost importance for the health risk assessment on inhaled airborne fine PM, given its inevitable contact with human circulatory system.

Perfluorohexadecanoic acid increases paracellular permeability in endothelial cells through the activation of plasma kallikrein-kinin system

Per- and polyfluoroalkyl substances (PFASs) are ubiquitous and high persistent in human blood, thus potentially inducing a myriad of deleterious consequences. Plasma kallikrein-kinin system (KKS), which physiologically regulates vascular permeability, is vulnerable to exogenous stimulators, like PFASs with long-chain alkyl backbone substituted by electronegative fluorine. The study on the interactions of PFASs with the KKS and the subsequent effects on vascular permeability would be helpful to illustrate how the chemicals penetrate the biological vascular barriers to reach different tissues. In present study, three representative PFASs, including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexadecanoic acid (PFHxDA), were investigated for their effects on the activation of the KKS, paracellular permeability in human retina endothelial cells (HRECs) and integrity of the adherens junctions. In contrast to either PFOS or PFOA, PFHxDA efficiently triggered KKS activation in a concentration-dependent manner based on protease activity assays. The plasma activated by PFHxDA significantly increased paracellular permeability of HRECs through the degradation of adherens junctions. As evidenced by the antagonistic effect of aprotinin, PFHxDA-involved effects on vascular permeability were mediated by KKS activation. The results herein firstly revealed the mechanistic pathway for PFHxDA induced effects on vascular endothelial cells. Regarding the possible structure-related activities of the chemicals, this finding would be of great help in the risk assessment of PFASs.

Mesothelial cells activate the plasma kallikrein-kinin system during pleural inflammation

Abstract Pleural inflammation underlies the formation of most exudative pleural effusions and the plasma kallikrein-kinin system (KKS) is known to contribute. Mesothelial cells are the predominant cell type in the pleural cavity, but their potential role in plasma KKS activation and BK production has not been studied. Bradykinin concentrations were higher in pleural fluids than the corresponding serum samples in patients with a variety of diseases. Bradykinin concentrations did not correlate with disease diagnosis, but were elevated in exudative effusions. It was demonstrated, using a range of primary and transformed mesothelial and mesothelioma cell lines, that cells assembled high molecular weight kininogen and plasma prekallikrein to liberate bradykinin, a process inhibited by novobiocin, a heat shock protein 90 (HSP90) inhibitor, cysteine, bradykinin and protamine sulphate. Of the common plasma prekallikrein activators, mesothelial cells expressed HSP90, but not prolylcarboxypeptidase or Factor XII. Calcium mobilisation was induced in some mesothelium-derived cell lines by bradykinin. Des-Arg(9)-bradykinin was inactive, indicating that mesothelial cells are responsive to bradykinin, mediated via the bradykinin receptor subtype 2. In summary, pleural mesothelial cells support the assembly and activation of the plasma KKS by a mechanism dependent on HSP90, and may contribute to KKS-mediated inflammation in pleural disease.

Contribution of the N-Terminal and C-Terminal Domains of Haemaphysalin to Inhibition of Activation of Plasma Kallikrein-Kinin System

Haemaphysalin is a kallikrein-kinin system inhibitor from hard tick Haemaphysalis longicornis, and consists of two Kunitz type protease inhibitor domains. Each domain as well as haemaphysalin inhibited intrinsic coagulation by inhibiting activation of the kallikrein-kinin system without affecting the amidolytic activities of intrinsic coagulation factors, indicating that both domains were involved in the inhibition through a similar mechanism to that for haemaphysalin. Reconstitution experiments showed that the C-terminal domain contributed more predominantly to this inhibition. Direct binding assaying showed that the C-terminal domain could bind to the cell-binding region of high molecular weight kininogen (HK), suggesting that it also binds to the cell-binding region of factor XII. Judging from these findings, the C-terminal domain may more effectively inhibit the association of factor XII and HK with the cell surface by binding to cell-binding regions, and hence would predominantly contribute to the inhibition of activation of the kallikrein-kinin system.

Activity of leukocyte elastase in patients' plasma is a significant indicator of atopic diseases

It is commonly known that activation of plasma kallikrein-kinin system is of great importance in the pathogenesis of atopic diseases. Plasma kallikrein most likely activates other arginine-esterases in human plasma. Diagnostic and prognostic values of the total arginine-esterase activity and the activity of leukocyte elastase (LE) in plasma of patients with allergic rhinitis (AR), atopic bronchial asthma (ABA) and atopic dermatitis (AD) were examined in this study. Our results demonstrate that the level of arginine-esterase activity was slightly elevated only in plasma of patients with ABA (424 ± 24; N-360 ± 20 mU/ml), but not with AR and AD. Elastase-like activity in human plasma proved to be a far more informative indicator of the atopic states than arginine-esterase activity. In plasma of patients with AR, ABA and AD the activity of LE exceeded the normal level in 1.7, 1.8, and 2.4 times, respectively. Treatment of these atopic states with Ditec (Boehringer Ingelheim) led to some improvements of the patient' states. The main component of this drug (disodium chromoglycate) inhibited the activity of leukocyte elastase in experiments in vitro.

Vascular Permeability Enhancement by Vibrio mimicus Protease and the Mechanisms of Action

Vibrio mimicus, a causative agent of gastroenteritis, has also been reported to attribute to extraintestinal infections. Recently we have purified a metalloprotease produced by the pathogen: however, the role of the protease in V. mimicus infection has not been documented. The V. mimicus protease (VMP) was found to enhance vascular permeability and form edema when injected into the dorsal skin of guinea pig and rat. The permeability enhancement by VMP was observed in a dose-dependent manner in both guinea pig and rat skin. In guinea pig, an inhibitor of the angiotensin-converting enzyme was found to augment the permeability enhancement reaction. The permeability enhancement was significantly blocked by soybean trypsin inhibitor (SBTI), an inhibitor of plasma kallikrein reaction. In vitro conversion of plasma prekallikrein to kallikrein by VMP was also noted. In rat skin, the permeability enhancement reaction was not blocked by antihistamine or SBTI. However, the reaction was partially blocked when a mixture of antihistamine and SBTI was administered with VMP. It is apparent from the study that in guinea pig skin, VMP enhances vascular permeability through activation of plasma kallikrein-kinin system which generates bradykinin, whereas in addition to the activation of plasma kallikrein-kinin cascade in the case of rat, stimulation of histamine release from mast cells and other unknown mechanism seem to be also a cause of the permeability enhancement reaction. These results suggest that VMP may play a role in extraintestinal infections with edema caused by the pathogen.

Activation of plasma kallikrein-kinin system and its significant role in pleural fluid accumulation of rat carrageenin-induced pleurisy.

Rat pleurisy was induced by intrapleural injection of lambda-carrageenin. The pleural exudate began to be accumulated 1-3 h after carrageenin administration and showed a peak at 19 h. The levels of prekallikrein and high-molecular-weight (HMW), but not low-molecular-weight (LMW), kininogen in the pleural fluid were markedly decreased when compared with those in plasma. Prekallikrein in rat plasma was activated by incubation with carrageenin in vitro. Captopril increased the plasma exudation significantly at 1-5 h. Depletion of prekallikrein and HMW kininogen in rat plasma by preadministration of bromelain caused marked inhibition of the plasma exudation at 1-24 h. The rest of the plasma exudation after bromelain was further decreased by simultaneous pretreatment of rats with both bromelain and aspirin. These results clearly indicate that plasma prekallikrein was activated in the pleural cavity and bradykinin released was responsible for plasma exudation during the entire course of this pleurisy.

Abnormalities of plasma kallikrein-kinin system in rat: low level of kinin release by kaolin activation.

Activation of plasma kallikrein-kinin system was examined in B/N-Katholiek rat,B/N-Kitasato and SD rat. [1] The activated thromboplastin time (APTT) was around 20 sec in SD and B/N-Ki, rut it was 35 sec in B/N-Ka.