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Frontiers in Physiology 2023Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are... (Review)
Review
Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are serine proteases from the same family, having high- and low-molecular weight kininogens (HKs and LKs) as substrates, releasing bradykinin (Bk) and Lys-bradykinin (Lys-Bk), respectively. This review presents a brief history of human PKa with details and recent observations of its evolution among the vertebrate coagulation proteins, including the relations with Factor XI. We explored the role of Factor XII in activating the plasma kallikrein-kinin system (KKS), the mechanism of activity and control in the KKS, and the function of HK on contact activation proteins on cell membranes. The role of human PKa in cell biology regarding the contact system and KSS, particularly the endothelial cells, and neutrophils, in inflammatory processes and infectious diseases, was also approached. We examined the natural plasma protein inhibitors, including a detailed survey of human PKa inhibitors' development and their potential market.
PubMed: 37711466
DOI: 10.3389/fphys.2023.1188816 -
Clinical and Experimental Immunology Dec 2023C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system....
C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system. In addition to the plasma leakage observed in hereditary angioedema (HAE), C1Inh deficiency may also affect these systems, which are important for thrombosis and inflammation. The aim of this study was to investigate the thromboinflammatory load in C1Inh deficiency. We measured 27 cytokines including interleukins, chemokines, interferons, growth factors, and regulators using multiplex technology. Complement activation (C4d, C3bc, and sC5b-C9/TCC), haemostatic markers (β-thromboglobulin (β-TG), thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), active plasminogen activator inhibitor-1 (PAI-1), and the neutrophil activation marker myeloperoxidase (MPO) were measured by enzyme immunoassays. Plasma and serum samples were collected from 20 patients with HAE type 1 or 2 in clinical remission and compared with 20 healthy age- and sex-matched controls. Compared to healthy controls, HAE patients had significantly higher levels of tumour necrosis factor (TNF), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, and IL-17A, chemokine ligand (CXCL) 8, chemokine ligand (CCL) 3, CCL4, IL-1 receptor antagonist (IL-1RA), granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor (FGF) 2 and platelet-derived growth factor (PDGF)-BB. HAE patients also had higher levels of TAT and F1 + 2. Although granulocyte colony-stimulating factor (G-CSF), β-TG and PAI-1 were higher in HAE patients, the differences did not reach statistical significance after correction for multiple testing. In conclusion, C1Inh deficiency is associated with an increased baseline thromboinflammatory load. These findings may reflect that HAE patients are in a subclinical attack state outside of clinically apparent oedema attacks.
Topics: Humans; Angioedemas, Hereditary; Plasminogen Activator Inhibitor 1; Ligands; Complement C1 Inhibitor Protein; Serpins; Interleukins; Chemokines
PubMed: 37561062
DOI: 10.1093/cei/uxad091 -
Frontiers in Immunology 2023Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid...
BACKGROUND
Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation.
METHODS
Citrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples.
RESULTS
C1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples.
CONCLUSION
Citrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems . Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.
Topics: Humans; Citrullination; Protein-Arginine Deiminases; Factor XIIa; Plasma Kallikrein; Factor XIa; Arthritis, Rheumatoid; Proteins; Autoantibodies
PubMed: 37426666
DOI: 10.3389/fimmu.2023.1203506 -
Frontiers in Cellular and Infection... 2023Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are... (Review)
Review
Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are responsible for the disease, infection accounts for most severe cases of the disease in humans. The mechanisms of cerebral malaria pathogenesis have been studied extensively in humans and animal malaria models; however, it is far from being fully understood. Recent discoveries indicate a potential role of bradykinin and the kallikrein kinin system in the pathogenesis of cerebral malaria. The aim of this review is to highlight how bradykinin is formed in cerebral malaria and how it may impact cerebral blood-brain barrier function. Areas of interest in this context include Plasmodium parasite enzymes that directly generate bradykinin from plasma protein precursors, cytoadhesion of infected red blood cells to brain endothelial cells, and endothelial cell blood-brain barrier disruption.
Topics: Animals; Humans; Bradykinin; Brain; Endothelial Cells; Malaria, Cerebral; Malaria, Falciparum
PubMed: 37637466
DOI: 10.3389/fcimb.2023.1184896 -
Allergology International : Official... Jul 2023Hereditary angioedema (HAE) is a rare disorder characterized by cutaneous and submucosal swelling caused mostly by excessive local bradykinin production. Bradykinin is a... (Review)
Review
Hereditary angioedema (HAE) is a rare disorder characterized by cutaneous and submucosal swelling caused mostly by excessive local bradykinin production. Bradykinin is a vasoactive peptide generated by the limited proteolysis of high molecular weight kininogen (HMWK) by plasma kallikrein via the contact activation system. The contact activation system occurs not only in solution but also on the cell surface. Factor XII (FXII), prekallikrein, and HMWK are assembled on the endothelial cell surface via several proteins, including a trimer of a receptor for globular C1q domain in a Zn-dependent manner, and the reciprocal activation on the cell surface is believed to be physiologically important in vivo. Thus, the contact activation system leads to the activation of coagulation, complement, inflammation, and fibrinolysis. C1-inhibitor (C1-INH) is a plasma protease inhibitor that is a member of the serpin family. It mainly inhibits activated FXII (FXIIa), plasma kallikrein, and C1s. C1-INH hereditary deficiency induces HAE (HAE-C1-INH) due to excessive bradykinin production via the incomplete inhibition of plasma kallikrein and FXIIa through the low C1-INH level. HAE is also observed in patients with normal C1-INH (HAEnCI) who carry pathogenic variants in genes of factor XII, plasminogen, angiopoietin 1, kininogen, myoferlin, and heparan sulfate 3-O-sulfotransferase 6, which are associated with bradykinin production and/or vascular permeability. HAE-causing pathways triggered by pathogenic variants in patients with HAE-C1-INH and HAEnCI are reviewed and discussed.
Topics: Humans; Angioedemas, Hereditary; Factor XII; Bradykinin; Plasma Kallikrein; Kininogen, High-Molecular-Weight; Complement C1 Inhibitor Protein; Molecular Biology
PubMed: 37169642
DOI: 10.1016/j.alit.2023.04.004 -
The World Allergy Organization Journal Jun 2023Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of... (Review)
Review
Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of swelling that typically affect the extremities, face, abdomen, genitals, and larynx. The most frequent cause of HAE is a mutation in the () gene, which either leads to deficient plasma levels of the C1-esterase inhibitor (C1-INH) protein (type I HAE-C1-INH) or normal plasma levels of dysfunctional C1-INH protein (type II HAE-C1-INH). Mutations in are known to be associated with dysregulation of the kallikrein-bradykinin cascade leading to enhancement of bradykinin production and increased vascular permeability. However, some patients present with a third type of HAE (HAE-nl-C1-INH) that is characterized by normal plasma levels and functionality of the C1-INH protein. While mutations in the , , , , , and genes have been identified in some patients with HAE-nI-C1-INH, genetic cause remains unknown in many cases with further research required to fully elucidate the pathology of disease in these patients. Here we review the challenges that arise on the pathway to a confirmed diagnosis of HAE and explore the multifactorial impact of receiving a HAE diagnosis. We conclude that it is important to continue to raise awareness of HAE because delays to diagnosis have a direct impact upon patient suffering and quality of life. Since many patients will seek help from hospitals during their first swelling attack it is vital that emergency department staff are aware of the different pathological pathways that distinguish HAE from other forms of angioedema to ensure that the most appropriate treatment is administered. As disease awareness increases, it is hoped that patients will be diagnosed earlier and that pre-authorization and insurance coverage of HAE treatments will become easier to obtain, ultimately reducing the burden of treatment for these patients and their caregivers.
PubMed: 37448849
DOI: 10.1016/j.waojou.2023.100792 -
Cureus Oct 2023Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway... (Review)
Review
Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independent mast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner's syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated with many FDA-approved targeted medications, such as plasma-derived C1-INH, plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant). However, these targeted agents are not well-studied enough to be used for acquired angioedema. It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments.
PubMed: 37927771
DOI: 10.7759/cureus.46536 -
Journal of Neuroinflammation Jun 2024Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key...
Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key component of the KKS - in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.
Topics: Animals; Recovery of Function; Male; Plasma Kallikrein; Mice; Mice, Inbred C57BL; Infarction, Middle Cerebral Artery; Blood-Brain Barrier; Stroke; Thrombosis; Ischemic Stroke; Inflammation
PubMed: 38872149
DOI: 10.1186/s12974-024-03149-w -
Frontiers in Medicine 2023SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and... (Review)
Review
SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity-conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS.
PubMed: 37448794
DOI: 10.3389/fmed.2023.1208866 -
Frontiers in Pharmacology 2023The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic...
The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic activities of FXIIa and single-chain Factor XII (FXII) zymogen contribute to KKS activation and thereby may play roles in both initiating and propagating HAE attacks. In this report, we investigated the effects of potent small molecule FXIIa inhibitors on FXIIa and single chain FXII enzymatic activities, KKS activation, and angioedema in mice. We examined the effects of 29 structurally distinct FXIIa inhibitors on enzymatic activities of FXIIa and a mutant single chain FXII with R334A, R343A and R353A substitutions (rFXII-T), that does not undergo zymogen conversion to FXIIa, using kinetic fluorogenic substrate assays. We examined the effects of a representative FXIIa inhibitor, KV998086, on KKS activation and both carrageenan- and captopril-induced angioedema in mice. FXIIa inhibitors designed to target its catalytic domain also potently inhibited the enzymatic activity of rFXII-T and the pICs of these compounds linearly correlated for rFXIIa and rFXII-T ( = 0.93). KV998086, a potent oral FXIIa inhibitor (IC = 7.2 nM) inhibited dextran sulfate (DXS)-stimulated generation of plasma kallikrein and FXIIa, and the cleavage of high molecular weight kininogen (HK) in human plasma. KV998086 also inhibited rFXII-T mediated HK cleavage ( < 0.005) in plasma from FXII knockout mice supplemented with rFXII-T and stimulated with polyphosphate or DXS. Orally administered KV998086 protected mice from 1) captopril-induced Evans blue leakage in colon and laryngotracheal tissues and 2) blocked carrageenan-induced plasma HK consumption and paw edema. These findings show that small molecule FXIIa inhibitors, designed to target its active site, also inhibit the enzymatic activity of FXII zymogen. Combined inhibition of FXII zymogen and FXIIa may thereby suppress both the initiation and amplification of KKS activation that contribute to hereditary angioedema attacks and other FXII-mediated diseases.
PubMed: 38178859
DOI: 10.3389/fphar.2023.1287487