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Medecine Sciences : M/S Dec 2019Monogenic diseases are rare genetic diseases but they are numerous and display a highly variable degree of severity. First uses of monoclonal antibodies to treat... (Review)
Review
Monogenic diseases are rare genetic diseases but they are numerous and display a highly variable degree of severity. First uses of monoclonal antibodies to treat monogenic diseases started in the 2000's and many clinical trials are ongoing. Anti-IL-1β therapies have greatly modified the outcome of auto-inflammatory diseases by modulating inflammatory response and reducing the risk of secondary amyloidosis. Anti-TNF-α are also used in such diseases. In atypical hemolytic and uremic syndrome due to deficiencies in the control of alternative complement pathway, eculizumab, an anti-C5 monoclonal antibody, has improved renal outcome in treated patients. More recently, lanadelumab, an anti-plasma kallikrein antibody, has reinforced the therapeutic arsenal in hereditary angioedema and burosumab, anti-FGF23, that of X-linked hypophosphatemia. Such examples reflect the importance of monoclonal antibody therapy of monogenic diseases, the interest of considering such an option as well as the need for future researches.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Fibroblast Growth Factor-23; Genetic Diseases, Inborn; Humans; Interleukin-1beta; Tumor Necrosis Factor-alpha
PubMed: 31903913
DOI: 10.1051/medsci/2019203 -
Cardiovascular & Hematological Agents... Jun 2012The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of...
PF-04886847 (an inhibitor of plasma kallikrein) attenuates inflammatory mediators and activation of blood coagulation in rat model of lipopolysaccharide (LPS)-induced sepsis.
The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide (LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg) prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced the elevated plasma 6-keto PGF1α levels in LPS treated rats, suggesting that PF-04886847 could be useful in preventing hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-α level. Pretreatment of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein (the zymogen form of plasma kallikrein) deficient patients have prolonged activated partial thromboplastin time (aPTT) without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847 was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events, PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both aPTT and prothrombin time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin mediated diseases.
Topics: Aminobenzoates; Aminopyridines; Animals; Blood Coagulation; Disease Models, Animal; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Inflammation Mediators; Lipopolysaccharides; Male; Plasma Kallikrein; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Sepsis; Thrombosis
PubMed: 22352684
DOI: 10.2174/187152512800388939 -
Comprehensive Physiology Apr 2011Autocrine, paracrine, endocrine, and neuroendocrine hormonal systems help regulate cardio-vascular and renal function. Any change in the balance among these systems may... (Review)
Review
Autocrine, paracrine, endocrine, and neuroendocrine hormonal systems help regulate cardio-vascular and renal function. Any change in the balance among these systems may result in hypertension and target organ damage, whether the cause is genetic, environmental or a combination of the two. Endocrine and neuroendocrine vasopressor hormones such as the renin-angiotensin system (RAS), aldosterone, and catecholamines are important for regulation of blood pressure and pathogenesis of hypertension and target organ damage. While the role of vasodepressor autacoids such as kinins is not as well defined, there is increasing evidence that they are not only critical to blood pressure and renal function but may also oppose remodeling of the cardiovascular system. Here we will primarily be concerned with kinins, which are oligopeptides containing the aminoacid sequence of bradykinin. They are generated from precursors known as kininogens by enzymes such as tissue (glandular) and plasma kallikrein. Some of the effects of kinins are mediated via autacoids such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and/or tissue plasminogen activator (tPA). Kinins help protect against cardiac ischemia and play an important part in preconditioning as well as the cardiovascular and renal protective effects of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARB). But the role of kinins in the pathogenesis of hypertension remains controversial. A study of Utah families revealed that a dominant kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. Moreover, researchers have identified a restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family found in one strain of spontaneously hypertensive rats (SHR) from a homologous gene in normotensive Brown Norway rats, and in recombinant inbred substrains derived from these SHR and Brown Norway rats this RFLP cosegregated with an increase in blood pressure. However, humans, rats and mice with a deficiency in one or more components of the kallikrein-kinin-system (KKS) or chronic KKS blockade do not have hypertension. In the kidney, kinins are essential for proper regulation of papillary blood flow and water and sodium excretion. B2-KO mice appear to be more sensitive to the hypertensinogenic effect of salt. Kinins are involved in the acute antihypertensive effects of ACE inhibitors but not their chronic effects (save for mineralocorticoid-salt-induced hypertension). Kinins appear to play a role in the pathogenesis of inflammatory diseases such as arthritis and skin inflammation; they act on innate immunity as mediators of inflammation by promoting maturation of dendritic cells, which activate the body's adaptive immune system and thereby stimulate mechanisms that promote inflammation. On the other hand, kinins acting via NO contribute to the vascular protective effect of ACE inhibitors during neointima formation. In myocardial infarction produced by ischemia/reperfusion, kinins help reduce infarct size following preconditioning or treatment with ACE inhibitors. In heart failure secondary to infarction, the therapeutic effects of ACE inhibitors are partially mediated by kinins via release of NO, while drugs that activate the angiotensin type 2 receptor act in part via kinins and NO. Thus kinins play an important role in regulation of cardiovascular and renal function as well as many of the beneficial effects of ACE inhibitors and ARBs on target organ damage in hypertension.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Physiological Phenomena; Humans; Kallikrein-Kinin System; Kidney
PubMed: 23737209
DOI: 10.1002/cphy.c100053 -
FASEB Journal : Official Publication of... Dec 2017The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon...
The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody-induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.-Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.
Topics: Animals; Arthritis; Autoantibodies; Bradykinin; Cytokines; Factor XII; Female; Humans; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Knockout; Monocytes; Plasma Kallikrein; Polymerase Chain Reaction
PubMed: 28808141
DOI: 10.1096/fj.201700018R -
The Journal of Allergy and Clinical... Mar 2024Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older.
OBJECTIVE
This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat.
METHODS
APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL).
RESULTS
Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n = 70), the mean (standard error) change in attack rate from baseline was -2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain.
CONCLUSION
Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.
Topics: Humans; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Double-Blind Method; Pyrazoles; Quality of Life; Treatment Outcome
PubMed: 38122865
DOI: 10.1016/j.jaip.2023.12.019 -
Journal of Thrombosis and Haemostasis :... Dec 2007The plasma kallikrein-kinin system consists of the proteins factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen. It was first recognized as a... (Review)
Review
The plasma kallikrein-kinin system consists of the proteins factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen. It was first recognized as a surface-activated coagulation system that is activated when blood or plasma interacts with artificial surfaces. Although surface-activated contact activation occurs in vivo in the case of tissue destruction or a developing thrombus, the physiologic basis for the activation and function of this system has not been delineated. New investigations indicate that there is a proteolytic pathway on cells for PK activation independent of FXII. This pathway for PK with subsequent FXII activation indicates physiologic activities. These activities include blood pressure regulation and modulation of thrombosis risk independently of hemostasis. Furthermore, they include regulation of endothelial cell proliferation, angiogenesis and apoptosis through a cellular-based, outside-in signaling system. The present characterizations of this system, which incorrectly had been thought to initiate coagulation, represent an evolution of understanding in this field.
Topics: Animals; Blood Coagulation; Blood Pressure; Bradykinin; Cell Proliferation; Endothelial Cells; Factor XII; Factor XIIa; Humans; Kininogen, High-Molecular-Weight; Neovascularization, Physiologic; Plasma Kallikrein; Prekallikrein; Regional Blood Flow; Risk Assessment; Signal Transduction; Thrombosis
PubMed: 17883591
DOI: 10.1111/j.1538-7836.2007.02770.x -
Novel contact-kinin inhibitor sylvestin targets thromboinflammation and ameliorates ischemic stroke.Cellular and Molecular Life Sciences :... Apr 2022Ischemic stroke is a leading cause of death and disability worldwide. Increasing evidence indicates that ischemic stroke is a thromboinflammatory disease in which the...
Ischemic stroke is a leading cause of death and disability worldwide. Increasing evidence indicates that ischemic stroke is a thromboinflammatory disease in which the contact-kinin pathway has a central role by activating pro-coagulant and pro-inflammatory processes. The blocking of distinct members of the contact-kinin pathway is a promising strategy to control ischemic stroke. Here, a plasma kallikrein and active FXII (FXIIa) inhibitor (sylvestin, contained 43 amino acids, with a molecular weight of 4790.4 Da) was first identified from forest leeches (Haemadipsa sylvestris). Testing revealed that sylvestin prolonged activated partial thromboplastin time without affecting prothrombin time. Thromboelastography and clot retraction assays further showed that it extended clotting time in whole blood and inhibited clot retraction in platelet-rich plasma. In addition, sylvestin prevented thrombosis in vivo in FeCl-induced arterial and carrageenan-induced tail thrombosis models. The potential role of sylvestin in ischemic stroke was evaluated by transient and permanent middle cerebral artery occlusion models. Sylvestin administration profoundly protected mice from ischemic stroke by counteracting intracerebral thrombosis and inflammation. Importantly, sylvestin showed no signs of bleeding tendency. The present study identifies sylvestin is a promising contact-kinin pathway inhibitor that can proffer profound protection from ischemic stroke without increased risk of bleeding.
Topics: Animals; Inflammation; Ischemic Stroke; Kinins; Mice; Stroke; Thromboinflammation; Thrombosis
PubMed: 35416530
DOI: 10.1007/s00018-022-04257-7 -
The Journal of Allergy and Clinical... Nov 2023Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and...
BACKGROUND
Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different hereditary angioedema-causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown.
OBJECTIVES
The aim was to describe trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants.
METHODS
HeLa cells were transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localization were carried out.
RESULTS
Our findings characterized functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into 5 different clusters, each containing variants sharing specific molecular characteristics. For all variants except 2, we found that coexpression of mutant and normal C1INH negatively affected the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci was detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH.
CONCLUSIONS
We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative disease mechanisms.
Topics: Humans; Complement C1 Inhibitor Protein; Angioedemas, Hereditary; HeLa Cells; Endopeptidases; Peptide Hydrolases
PubMed: 37301409
DOI: 10.1016/j.jaci.2023.04.023 -
Journal of Thrombosis and Haemostasis :... Jan 2019Essentials During contact system activation, factor XII is progressively cleaved by plasma kallikrein. We investigated the role of factor XII truncation in biochemical...
Essentials During contact system activation, factor XII is progressively cleaved by plasma kallikrein. We investigated the role of factor XII truncation in biochemical studies. Factor XII contains naturally occurring truncating cleavage sites for a variety of enzymes. Truncation of factor XII primes it for activation in solution through exposure of R353. SUMMARY: Background The contact activation system and innate immune system are interlinked in inflammatory pathology. Plasma kallikrein (PKa) is held responsible for the stepwise processing of factor XII (FXII). A first cleavage activates FXII (into FXIIa); subsequent cleavages truncate it. This truncation eliminates its surface-binding domains, which negatively regulates surface-dependent coagulation. Objectives To investigate the influence of FXII truncation on its activation and downstream kallikrein-kinin system activation. Methods We study activation of recombinant FXII variants by chromogenic assays, by FXIIa ELISA and western blotting. Results We demonstrate that FXII truncation primes it for activation by PKa in solution. We demonstrate this phenomenon in three settings. (i) Truncation at a naturally occurring PKa-sensitive cleavage site, R334, accelerates FXIIa formation in solution. A site-directed mutant FXII-R334A displays ~50% reduced activity when exposed to PKa. (ii) A pathogenic mutation in FXII that causes hereditary angioedema, introduces an additional plasmin-sensitive cleavage site. Truncation at this site synergistically accelerates FXII activation in solution. (iii) We identify new, naturally occurring cleavage sites in FXII that have so far not been functionally linked to contact system activation. As examples, we show that non-activating truncation of FXII by neutrophil elastase and cathepsin K primes it for activation by PKa in solution. Conclusions FXII truncation, mediated by either pathogenic mutations or naturally occurring cleavage sites, primes FXII for activation in solution. We propose that the surface-binding domains of FXII shield its activating cleavage site, R353. This may help to explain how the contact system contributes to inflammatory pathology.
Topics: Blood Coagulation; Cathepsin K; Enzyme Activation; Factor XII; Factor XIIa; HEK293 Cells; Humans; Leukocyte Elastase; Mutation; Plasma Kallikrein; Proline-Rich Protein Domains; Protein Interaction Domains and Motifs; Substrate Specificity; Time Factors
PubMed: 30394658
DOI: 10.1111/jth.14325 -
British Journal of Pharmacology Sep 19681. This investigation was designed to re-examine the possibility that anti-inflammatory steroids interfere with the kinin-forming system.2. We conclude that the...
1. This investigation was designed to re-examine the possibility that anti-inflammatory steroids interfere with the kinin-forming system.2. We conclude that the anti-inflammatory action of corticosteroids cannot be explained by the inhibition of kinin formation. This view is based on the following findings.3. Neither hydrocortisone nor prednisolone nor dexamethasone inhibited the activation or activity of intrinsic plasma kinin forming enzymes resulting from dilution, incubation with kininase inhibitors, or exposure to glass, monosodium urate microcrystals or to precipitated complexes of rheumatoid factor and aggregated human gamma-globulin.4. Hydrocortisone did not inhibit the action of the active kinin-forming enzymes, human salivary or urinary kallikrein, or plasmin on purified kininogen.5. Hydrocortisone, prednisolone and dexamethasone did not inhibit the hydrolysis of benzoyl-arginine-ethyl ester by human plasmin, plasma kallikrein or hog pancreatic kallikrein.6. Kinin formation occurred normally in plasma taken from two patients receiving betamethasone and one receiving prednisone.
Topics: Animals; Arginine; Betamethasone; Dexamethasone; Esters; Fibrinolysin; Glass; Glucocorticoids; Guinea Pigs; Humans; Hydrocortisone; In Vitro Techniques; Kallikreins; Kinins; Pancreas; Plasma; Prednisolone; Prednisone; Rats; Rheumatoid Factor; Saliva; gamma-Globulins
PubMed: 4175457
DOI: 10.1111/j.1476-5381.1968.tb07960.x