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Microorganisms Sep 2022We aimed to determine the biomarker performance of the proteolytic enzymes cathepsin B (Cat B) and plasma kallikrein (PKa) and transforming growth factor (TGF)-β to...
We aimed to determine the biomarker performance of the proteolytic enzymes cathepsin B (Cat B) and plasma kallikrein (PKa) and transforming growth factor (TGF)-β to detect hepatic fibrosis (HF) in chronic hepatitis C (CHC) patients. We studied 53 CHC patients and 71 healthy controls (HCs). Hepatic-disease stage was determined by liver biopsies, aminotransferase:platelet ratio index (APRI) and Fibrosis (FIB)4. Hepatic inflammation and HF in CHC patients were stratified using the METAVIR scoring system. Cat-B and PKa activities were monitored fluorometrically. Serum levels of TGF-β (total and its active form) were determined using ELISA-like fluorometric methods. Increased serum levels of Cat B and PKa were found (p < 0.0001) in CHC patients with clinically significant HF and hepatic inflammation compared with HCs. Levels of total TGF-β (p < 0.0001) and active TGF-β (p < 0.001) were increased in CHC patients compared with HCs. Cat-B levels correlated strongly with PKa levels (r = 0.903, p < 0.0001) in CHC patients but did not correlate in HCs. Levels of Cat B, PKa and active TGF-β increased with the METAVIR stage of HF. Based on analyses of receiver operating characteristic (ROC) curves, Cat B and PKa showed high diagnostic accuracy (area under ROC = 0.99 ± 0.02 and 0.991 ± 0.007, respectively) for distinguishing HF in CHC patients from HCs. Taken together, Cat B and PKa could be used as circulating biomarkers to detect HF in HCV-infected patients.
PubMed: 36144371
DOI: 10.3390/microorganisms10091769 -
Investigative Ophthalmology & Visual... May 2016Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the...
PURPOSE
Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema.
METHODS
Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy.
RESULTS
Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice.
CONCLUSIONS
Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
Topics: Animals; Blotting, Western; Capillary Permeability; Intravitreal Injections; Macular Edema; Male; Mice; Mice, Inbred C57BL; Plasma Kallikrein; Rats; Rats, Sprague-Dawley; Retina; Tomography, Optical Coherence; Vascular Endothelial Growth Factor A
PubMed: 27138737
DOI: 10.1167/iovs.15-18272 -
ACS Medicinal Chemistry Letters Aug 2017
PubMed: 28835783
DOI: 10.1021/acsmedchemlett.7b00253 -
Diabetes Nov 2020We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the Diabetes...
We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983-1989), midpoint (1988-1991), and end (1993) and at EDIC years 4-6 (1997-1999), 8-10 (2001-2003), and 11-13 (2004-2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (hazard ratio [HR] = 1.16 per 20 nmol/L higher levels of plasma kallikrein; = 0.0177) as well as over the EDIC-only period (HR = 1.22; = 0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA (HR = 1.20; = 0.0082) and in the fully adjusted model for other CVD risk factors (HR = 1.17; = 0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in the unadjusted (HR = 1.25; = 0.0145), minimally adjusted (HR = 1.23; = 0.0417, and fully adjusted (HR = 1.27; = 0.0328) models for EDIC only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.
Topics: Adult; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 1; Female; Humans; Kallikreins; Longitudinal Studies; Male; Risk Factors; Young Adult
PubMed: 32826295
DOI: 10.2337/db20-0427 -
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 -
International Immunopharmacology Feb 2008The plasma kallikrein/kinin system that consists of the proteins factor XII, prekallikrein, and high molecular weight kininogen was first recognized as a... (Review)
Review
The plasma kallikrein/kinin system that consists of the proteins factor XII, prekallikrein, and high molecular weight kininogen was first recognized as a surface-activated coagulation system arising when blood or plasma interacts with artificial surfaces. Although surface-activated contact activation occurs in vivo when various negatively charged surfaces become exposed, including a developing platelet thrombus, a physiologic, non-injury mechanism for activation, regulation, and function of this system has been elusive. Recent investigations have shown that there is a physiologic pathway for assembly and activation of this system independent of factor XII. Gene deficient mice of the bradykinin B2 receptor and factor XII have been recognized to have reduced risk for arterial thrombosis. This plasma proteolytic system influences arterial thrombosis independent of influencing hemostasis. Thus, the plasma kallikrein/kinin system has two mechanisms for its activation: one that is dependent and another independent of factor XII. Better understanding of this system may lead to insight into mechanisms for arterial thrombosis, independent of hemostasis.
Topics: Animals; Factor XII; Humans; Kallikrein-Kinin System; Receptor, Bradykinin B2; Thrombosis
PubMed: 18182220
DOI: 10.1016/j.intimp.2007.08.022 -
Blood Feb 2020
Topics: Kallikreins; Plasma Kallikrein; Prekallikrein; Proteolysis
PubMed: 32078685
DOI: 10.1182/blood.2019004339 -
Frontiers in Immunology 2019Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a... (Review)
Review
Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function. A growing body of evidence has revealed that both FXII and FXIIa upregulate neutrophil functions, contribute to macrophage polarization and induce T-cell differentiation. , these signaling activities contribute to host defense against pathogens, mediate the development of neuroinflammation, influence wound repair and may facilitate cancer maintenance and progression. Here, we review the roles of FXII in innate immunity as they relate to non-sterile and sterile immune responses.
Topics: Animals; Blood Coagulation; Bradykinin; Disease Susceptibility; Extracellular Traps; Factor XII; Humans; Immunity, Innate; Immunomodulation; Neutrophils; Plasma Kallikrein; Wound Healing
PubMed: 31507606
DOI: 10.3389/fimmu.2019.02011 -
Journal of Thrombosis and Haemostasis :... Jan 2016The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of... (Review)
Review
The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of the blood coagulation, fibrinolytic, complement and renin-angiotensin fields. These proteins initially were proposed as part of the hemostatic pathways because their deficiencies are associated with prolonged clinical assays. However, the absence of bleeding states with deficiencies of factor XII (FXII), prekallikrein (PK) and high-molecular-weight kininogen indicates that the CAS and KKS do not contribute to hemostasis. Since the discovery of the Hageman factor 60 years ago much has been learned about the biochemistry, cell biology and animal physiology of these proteins. The CAS is a pathophysiologic surface defense mechanism against foreign proteins, organisms and artificial materials. The KKS is an inflammatory response mechanism. Targeting their activation through FXIIa or plasma kallikrein inhibition when blood interacts with the artificial surfaces of modern interventional medicine or in acute attacks of hereditary angioedema restores vascular homeostasis. FXII/FXIIa and products that arise with PK deficiency also offer novel ways to reduce arterial and venous thrombosis without an effect on hemostasis. In summary, there is revived interest in the CAS and KKS due to better understanding of their activities. The new appreciation of these systems will lead to several new therapies for a variety of medical disorders.
Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Bradykinin; Factor XII; Factor XIIa; Hemostasis; Homeostasis; Humans; Inflammation; Kallikrein-Kinin System; Kininogen, High-Molecular-Weight; Mice; Plasma Kallikrein; Prekallikrein; Receptors, Bradykinin; Thrombosis
PubMed: 26565070
DOI: 10.1111/jth.13194 -
Allergology International : Official... Jan 2023Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and... (Review)
Review
Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.
Topics: Humans; Antibodies, Monoclonal; Plasma Kallikrein; Angioedemas, Hereditary; Treatment Outcome; Complement C1 Inhibitor Protein; Bradykinin
PubMed: 35787344
DOI: 10.1016/j.alit.2022.06.001