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Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency.
Front Immunol 2018; 9:2183FI

Abstract

Multiple pathways have been proposed to generate bradykinin (BK)-related peptides from blood. We applied various forms of activation to fresh blood obtained from 10 healthy subjects or 10 patients with hereditary angioedema (HAE-1 or -2 only) to investigate kinin formation. An enzyme immunoassay for BK was applied to extracts of citrated blood incubated at 37°C under gentle agitation for 0-2 h in the presence of activators and/or inhibitory agents. Biologically active kinins in extracts were corroborated by c-Fos accumulation in HEK 293a cells that express either recombinant human B2 or B1 receptors (B2R, B1R). Biological evidence of HAE diagnostic and blood cell activation was also obtained. The angiotensin converting enzyme inhibitor enalaprilat, without any effect per se, increased immunoreactive BK (iBK) concentration under active stimulation of blood. Tissue kallikrein (KLK-1) and Kontact-APTT, a particulate material that activates the contact system, rapidly (5 min) and intensely (>100 ng/mL) induced similar iBK generation in the blood of control or HAE subjects. Tissue plasminogen activator (tPA) slowly (≥1 h) induced iBK generation in control blood, but more rapidly and intensely so in that of HAE patients. Effects of biotechnological inhibitors indicate that tPA recruits factor XIIa (FXIIa) and plasma kallikrein to generate iBK. KLK-1, independent of the contact system, is the only stimulus leading to an inconsistent B1R stimulation. Stimulating neutrophils or platelets did not generate iBK. In the HAE patients observed during remission, iBK formation capability coupled to B2R stimulation appears largely intact. However, a selective hypersensitivity to tPA in the blood of HAE patients suggests a role of plasmin-activated FXIIa in the development of attacks. Proposed pathways of kinin formation dependent on blood cell activation were not corroborated.

Authors+Show Affiliations

Axe Microbiologie-Infectiologie et Immunologie, CHU de Québec-Université Laval, Québec, QC, Canada.Service d'allergie, CHU de Québec-Université Laval, Québec, QC, Canada.Division of Hematology/Oncology, CHU Sainte-Justine, Montréal, QC, Canada.Division of Hematology/Oncology, CHU Sainte-Justine, Montréal, QC, Canada.Axe Microbiologie-Infectiologie et Immunologie, CHU de Québec-Université Laval, Québec, QC, Canada.Axe Microbiologie-Infectiologie et Immunologie, CHU de Québec-Université Laval, Québec, QC, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30333824

Citation

Charest-Morin, Xavier, et al. "Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency." Frontiers in Immunology, vol. 9, 2018, p. 2183.
Charest-Morin X, Hébert J, Rivard GÉ, et al. Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Front Immunol. 2018;9:2183.
Charest-Morin, X., Hébert, J., Rivard, G. É., Bonnefoy, A., Wagner, E., & Marceau, F. (2018). Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Frontiers in Immunology, 9, p. 2183. doi:10.3389/fimmu.2018.02183.
Charest-Morin X, et al. Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Front Immunol. 2018;9:2183. PubMed PMID: 30333824.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency. AU - Charest-Morin,Xavier, AU - Hébert,Jacques, AU - Rivard,Georges-Étienne, AU - Bonnefoy,Arnaud, AU - Wagner,Eric, AU - Marceau,François, Y1 - 2018/10/02/ PY - 2018/06/25/received PY - 2018/09/04/accepted PY - 2018/10/19/entrez PY - 2018/10/20/pubmed PY - 2018/10/20/medline KW - B2 receptors KW - bradykinin KW - hereditary angioedema with C1 inhibitor deficiency KW - kallikreins KW - tissue plasminogen activator SP - 2183 EP - 2183 JF - Frontiers in immunology JO - Front Immunol VL - 9 N2 - Multiple pathways have been proposed to generate bradykinin (BK)-related peptides from blood. We applied various forms of activation to fresh blood obtained from 10 healthy subjects or 10 patients with hereditary angioedema (HAE-1 or -2 only) to investigate kinin formation. An enzyme immunoassay for BK was applied to extracts of citrated blood incubated at 37°C under gentle agitation for 0-2 h in the presence of activators and/or inhibitory agents. Biologically active kinins in extracts were corroborated by c-Fos accumulation in HEK 293a cells that express either recombinant human B2 or B1 receptors (B2R, B1R). Biological evidence of HAE diagnostic and blood cell activation was also obtained. The angiotensin converting enzyme inhibitor enalaprilat, without any effect per se, increased immunoreactive BK (iBK) concentration under active stimulation of blood. Tissue kallikrein (KLK-1) and Kontact-APTT, a particulate material that activates the contact system, rapidly (5 min) and intensely (>100 ng/mL) induced similar iBK generation in the blood of control or HAE subjects. Tissue plasminogen activator (tPA) slowly (≥1 h) induced iBK generation in control blood, but more rapidly and intensely so in that of HAE patients. Effects of biotechnological inhibitors indicate that tPA recruits factor XIIa (FXIIa) and plasma kallikrein to generate iBK. KLK-1, independent of the contact system, is the only stimulus leading to an inconsistent B1R stimulation. Stimulating neutrophils or platelets did not generate iBK. In the HAE patients observed during remission, iBK formation capability coupled to B2R stimulation appears largely intact. However, a selective hypersensitivity to tPA in the blood of HAE patients suggests a role of plasmin-activated FXIIa in the development of attacks. Proposed pathways of kinin formation dependent on blood cell activation were not corroborated. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/30333824/Comparing_Pathways_of_Bradykinin_Formation_in_Whole_Blood_From_Healthy_Volunteers_and_Patients_With_Hereditary_Angioedema_Due_to_C1_Inhibitor_Deficiency_ L2 - https://doi.org/10.3389/fimmu.2018.02183 DB - PRIME DP - Unbound Medicine ER -