scholarly journals In Vitro Modeling of Bradykinin-Mediated Angioedema States

2020 ◽  
Vol 13 (9) ◽  
pp. 201
Author(s):  
François Marceau ◽  
Hélène Bachelard ◽  
Xavier Charest-Morin ◽  
Jacques Hébert ◽  
Georges E. Rivard
Keyword(s):  
Analytical Techniques ◽  
Ace Inhibition ◽  
Factor Xii ◽  
Kinin System ◽  
Angiotensin I Converting Enzyme ◽  
B1 Receptor ◽  
Kallikrein Kinin System ◽  
Esterase Inhibitor

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

Factor XII Contact Activation

2017 ◽  
Vol 43 (08) ◽  
pp. 814-826 ◽  
Author(s):  
Clément Naudin ◽  
Elena Burillo ◽  
Stefan Blankenberg ◽  
Lynn Butler ◽  
Thomas Renné
Keyword(s):  
Critical Role ◽  
Factor Xii ◽  
Contact Activation ◽  
Kinin System ◽  
Disease States ◽  
Charged Surfaces ◽  
Mechanistic Basis ◽  
Kallikrein Kinin System

AbstractContact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation–associated disease states.

Role of kallikrein-kinin system in pathogenesis of bacterial cell wall-induced inflammation

1991 ◽  
Vol 260 (2) ◽  
pp. G213-G219 ◽  
Author(s):  
R. A. DeLa Cadena ◽  
K. J. Laskin ◽  
R. A. Pixley ◽  
R. B. Sartor ◽  
J. H. Schwab ◽  
...  
Keyword(s):  
Cell Wall ◽  
Acute Phase ◽  
Bacterial Cell ◽  
Chronic Phase ◽  
Bacterial Cell Wall ◽  
Kinin System ◽  
Kallikrein Kinin System ◽  
Bacterial Products

The plasma kallikrein-kinin system is activated in Gram-negative sepsis and typhoid fever, two diseases in which bacterial products have been shown to initiate inflammation. Because a single intraperitoneal injection of bacterial cell wall peptidoglycan-polysaccharide polymers from group A steptococci (PG-APS) into a Lewis rat produces a syndrome of relapsing polyarthritis and anemia, we investigated changes in the role of the kallikrein-kinin system in this model of inflammation. Coagulation studies after injection of PG-APS revealed an immediate and persistent decrease in prekallikrein levels. High-molecular-weight kininogen levels decreased significantly during the acute phase and correlated with the severity of arthritis. Factor XI levels were decreased only during the acute phase. Antithrombin III levels remained unchanged, indicating that neither decreased hepatic synthesis nor disseminated intravascular coagulation caused the decreased plasma contact factors. Plasma T-kininogen (an acute phase protein) was significantly elevated during the chronic phase. PG-APS failed to activate the contact system in vitro. Thus the kallikrein-kinin system plays an important role in this experimental model of inflammation, suggesting that activation of this system may play a role in the pathogenesis of inflammatory bowel disease and rheumatoid arthritis in which bacterial products might be etiologically important.

Plasma Kallikrein-Kinin System in Patients with Uncomplicated Sepsis and Septic Shock-Comparison with Cardiogenic Shock

1987 ◽  
Vol 58 (02) ◽  
pp. 709-713 ◽  
Author(s):  
F Martínez-Brotóns ◽  
J R Oncins ◽  
J Mestres ◽  
V Amargós ◽  
C Reynaldo
Keyword(s):  
Septic Shock ◽  
Cardiogenic Shock ◽  
Antithrombin Iii ◽  
Factor Xii ◽  
Kinin System ◽  
Normal Limits ◽  
At Iii ◽  
Sepsis And Septic Shock ◽  
Kallikrein Kinin System ◽  
Esterase Inhibitor

SummaryAlterations of the kallikrein-kinin system consistent with activation and increased consumption have been re2ported in septic patients and it has been suggested that this activation could contribute to the development of septic shock.The aim of this work was to confirm these alterations in septic patients and to investigate the possible existence of similar changes in subjects developing cardiogenic shock secondary to myocardial infarction as a model of non septic shock.Patients with septic shock, especially in fatal cases, showed a highly significant decrease in levels of factor XII, prekallikrein, high molecular weight kininogen (HMW-kininogen), α2-macro-globulin (α2-M) and antithrombin III (AT-III). C1-esterase inhibitor (C1-INH) activity was increased in uncomplicated sepsis but came back to normal or was slightly decreased in septic shock.Components and inhibitors of the kallikrein-kinin system were within normal limits in patients with cardiogenic shock.Our findings support the idea of a contribution of the kallikrein-kinin system to the development of septic shock though this system does not seem to play a significant role in the pathogenesis of cardiogenic shock or seem to be altered as a consequence of it.

Development of diabetic cardiomyopathy and the kallikrein-kinin system – new insights from B1 and B2 receptor signaling

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Carsten Tschöpe ◽  
Dirk Westermann
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Calcium Handling ◽  
Kinin System ◽  
Cardiac Inflammation ◽  
B1 Receptor ◽  
Kinin Receptors ◽  
Patients With Diabetes ◽  
Underlying Mechanisms ◽  
Kallikrein Kinin System

Abstract Diabetic cardiomyopathy is a specific cardiomyopathy which develops in patients with diabetes mellitus in the absence of coronary atherosclerosis and hypertension. Despite the potential importance of this disease entity, the underlying mechanisms are only incompletely understood. Changes in calcium handling, disruption of the extracellular matrix regulation with accumulation of cardiac collagen, and furthermore cardiac inflammation may be an important mediator of this disease. This brief review focuses on the current aspects of the kallikrein-kinin system and its influence on the development of diabetic cardiomyopathy with particular regard to the kinin receptors B1 and B2, as their role in the development of this disease is still under discussion. Whether the role of the B1 receptor is similar to the well-described beneficial role of the B2 receptor or whether its function is opposed to the B2 receptor is controversial. Some recent findings suggest that the B1 receptor mediates cardiac inflammation and therefore may be detrimental for cardiac function in the setting of diabetic cardiomyopathy.

scholarly journals Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

2014 ◽  
Vol 221 (2) ◽  
pp. 297-308 ◽  
Author(s):  
Louis Potier ◽  
Ludovic Waeckel ◽  
Fréderic Fumeron ◽  
Sophie Bodin ◽  
Marinos Fysekidis ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Tissue Kallikrein ◽  
Loss Of Function ◽  
Kinin System ◽  
Angiotensin I Converting Enzyme ◽  
General Population Cohort ◽  
Kallikrein Kinin System ◽  
Changes Over Time

The kallikrein–kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinin-inactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of theTKgene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptin-deficient (ob/ob) mice to generate doubleob/ob-TK-deficient mutants. In man, a loss-of-function polymorphism of theTKgene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise,ob-TK−/−mice had similar GTT and ITT responses to those ofob-TK+/+mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes.

scholarly journals The bradykinin system in stress and anxiety in humans and mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ari Rouhiainen ◽  
Natalia Kulesskaya ◽  
Marie Mennesson ◽  
Zuzanna Misiewicz ◽  
Tessa Sipilä ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Stress Responses ◽  
Receptor Gene ◽  
Kinin System ◽  
Mediated Effects ◽  
B1 Receptor ◽  
Brown Adipose ◽  
Approach Avoidance ◽  
Kallikrein Kinin System

AbstractPharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.

scholarly journals Treatment of Hereditary Angioedema

2021 ◽  
Vol 31 (1) ◽  
pp. 1-16
Author(s):  
T Caballero
Keyword(s):  
Hereditary Angioedema ◽  
New Drugs ◽  
Current Therapy ◽  
Factor Xii ◽  
Short Term ◽  
Kinin System ◽  
C1 Esterase Inhibitor ◽  
Kallikrein Kinin System ◽  
Esterase Inhibitor

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti–activated FXII action.

scholarly journals Kinins and Kinin Receptors in Cardiovascular and Renal Diseases

2021 ◽  
Vol 14 (3) ◽  
pp. 240
Author(s):  
Jean-Pierre Girolami ◽  
Nadine Bouby ◽  
Christine Richer-Giudicelli ◽  
Francois Alhenc-Gelas
Keyword(s):  
Experimental Studies ◽  
Physiological Role ◽  
Renal Diseases ◽  
Kinin System ◽  
Genetic Studies ◽  
Pharmacological Manipulation ◽  
Kininase Ii ◽  
Kinin Receptors ◽  
Kallikrein Kinin System

This review addresses the physiological role of the kallikrein–kinin system in arteries, heart and kidney and the consequences of kallikrein and kinin actions in diseases affecting these organs, especially ischemic and diabetic diseases. Emphasis is put on pharmacological and genetic studies targeting kallikrein; ACE/kininase II; and the two kinin receptors, B1 (B1R) and B2 (B2R), distinguished through the work of Domenico Regoli and his collaborators. Potential therapeutic interest and limitations of the pharmacological manipulation of B1R or B2R activity in cardiovascular and renal diseases are discussed. This discussion addresses either the activation or inhibition of these receptors, based on recent clinical and experimental studies.

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