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Clinical Reviews in Allergy & Immunology Jun 2021In the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of... (Review)
Review
In the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of bradykinin has been studied thoroughly; however, numerous questions remained open regarding the triggering, course, and termination of angioedema attacks. Recently, it became clear that vascular endothelial cells have an integrative role in the regulation of vessel permeability. Apart from bradykinin, a great number of factors of different origin, structure, and mechanism of action are capable of modifying the integrity of vascular endothelium, and thus, may participate in the regulation of angioedema formation. Our aim in this review is to describe the most important permeability factors and the molecular mechanisms how they act on endothelial cells. Based on endothelial cell function, we also attempt to explain some of the challenging findings regarding bradykinin-mediated angioedema, where the function of bradykinin itself cannot account for the pathophysiology. By deciphering the complex scenario of vascular permeability regulation and edema formation, we may gain better scientific tools to be able to predict and treat not only bradykinin-mediated but other types of angioedema as well.
Topics: Angioedema; Bradykinin; Capillary Permeability; Endothelial Cells; Humans; Transcription Factors
PubMed: 33725263
DOI: 10.1007/s12016-021-08851-8 -
Frontiers in Endocrinology 2022Bradykinin (BK) and its biologically active metabolite des-Arg9 bradykinin (DABK) play a pivotal role in inflammation. Since chorioamnionitis is the leading cause of...
The Bradykinin System Contributes to the Regulation of Prostaglandin-Endoperoxide Synthase 2 Expression in Human Amnion Fibroblasts: Implications for Term and Preterm Birth.
BACKGROUND
Bradykinin (BK) and its biologically active metabolite des-Arg9 bradykinin (DABK) play a pivotal role in inflammation. Since chorioamnionitis is the leading cause of preterm birth and prostaglandin E2 (PGE2) derived from the amnion is key to labor initiation, we investigated if bradykinin peptides are part of the regulatory network of PGE2 synthesis in human amnion at parturition.
METHODS
Human amnion tissue was obtained from term and preterm birth for the study of the changes of the bradykinin system at parturition. Cultured primary human amnion fibroblasts, the major source of PGE2, were used to study the effects of bradykinin peptides on PTGS2 expression and PGE2 production as well as the effects of infection mediators on bradykinin receptors.
RESULTS
Bradykinin peptides and their receptors BDKRB1 and BDKRB2 were present in human amnion, and their abundance increased in term and preterm labor. However, transcripts of the genes encoding the bradykinin precursor and its proteolytic cleavage enzymes were hardly detectable in human amnion despite the increased abundance of bradykinin peptides in term and preterm labor, suggesting that there is an alternative source of bradykinin peptides for human amnion and their actions are enhanced in human amnion at parturition. studies in cultured human amnion fibroblasts showed that both BK and DABK increased the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme in prostaglandin synthesis, and subsequent PGE2 production. These effects of BK and DABK were mediated through BDKRB2 and BDKRB1 receptors, respectively, with subsequent activation of the p38 and ERK1/2 pathways. Moreover, lipopolysaccharide (LPS) and serum amyloid A1 (SAA1), the important mediators of infectious inflammation, induced the expression of both BDKRB1 and BDKRB2 through toll-like receptor 4 (TLR4). Induction of BDKRB1 and BDKRB2 expression by LPS and SAA1 enhanced BK- or DABK-induced PTGS2 expression and PGE2 production in human amnion fibroblasts.
CONCLUSIONS
This study demonstrated for the first time that the human amnion is a target tissue of bradykinin peptides and the bradykinin system may be part of the regulatory network of PTGS2 expression and PGE2 production in human amnion fibroblasts at both term and preterm birth, which may be enhanced by infection.
Topics: Amnion; Bradykinin; Cyclooxygenase 2; Dinoprostone; Female; Fibroblasts; Humans; Infant, Newborn; Inflammation; Lipopolysaccharides; Obstetric Labor, Premature; Pregnancy; Premature Birth; Transcription Factors
PubMed: 35634493
DOI: 10.3389/fendo.2022.873727 -
Nature Communications Feb 2022The type 2 bradykinin receptor (B2R) is a G protein-coupled receptor (GPCR) in the cardiovascular system, and the dysfunction of B2R leads to inflammation, hereditary...
The type 2 bradykinin receptor (B2R) is a G protein-coupled receptor (GPCR) in the cardiovascular system, and the dysfunction of B2R leads to inflammation, hereditary angioedema, and pain. Bradykinin and kallidin are both endogenous peptide agonists of B2R, acting as vasodilators to protect the cardiovascular system. Here we determine two cryo-electron microscopy (cryo-EM) structures of human B2R-G in complex with bradykinin and kallidin at 3.0 Å and 2.9 Å resolution, respectively. The ligand-binding pocket accommodates S-shaped peptides, with aspartic acids and glutamates as an anion trap. The phenylalanines at the tail of the peptides induce significant conformational changes in the toggle switch W283, the conserved PIF, DRY, and NPxxY motifs, for the B2R activation. This further induces the extensive interactions of the intracellular loops ICL2/3 and helix 8 with G proteins. Our structures elucidate the molecular mechanisms for the ligand binding, receptor activation, and G proteins coupling of B2R.
Topics: Amino Acid Sequence; Binding Sites; Bradykinin; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Kallidin; Ligands; Models, Molecular; Protein Binding; Protein Interaction Domains and Motifs; Receptor, Bradykinin B2
PubMed: 35132089
DOI: 10.1038/s41467-022-28399-1 -
Journal of Biochemical and Molecular... Dec 2022Stroke is a life-threatening disease with limited therapeutic options. Damage to the blood-brain barrier (BBB) is the key pathological feature of ischemic stroke. This...
Stroke is a life-threatening disease with limited therapeutic options. Damage to the blood-brain barrier (BBB) is the key pathological feature of ischemic stroke. This study explored the role of the bradykinin (BK)/bradykinin 1 receptor (B1R) and its mechanism of action in the BBB. Human brain microvascular endothelial cells (BMECs) were used to test for cellular responses to BK by using the Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, enzyme-linked immunosorbent assay, flow cytometry, immunofluorescence, cellular permeability assays, and western blotting to evaluate cell viability, cytokine production, and reactive oxygen species (ROS) levels in vitro. A BBB induced by middle cerebral artery occlusion was used to evaluate BBB injuries, and the role played by BK/B1R in ischemic/reperfusion (I/R) was explored in a rat model. Results showed that BK reduced the viability of BMECs and increased the levels of proinflammatory cytokines (interleukin 6 [IL-6], IL-18, and monocyte chemoattractant protein-1) and ROS. Additionally, cellular permeability was increased by BK treatment, and the expression of tight junction proteins (claudin-5 and occludin) was decreased. Interestingly, Wnt3a expression was inhibited by BK and exogenous Wnt3a restored the effects of BK on BMECs. In an in vivo I/R rat model, knockdown of B1R significantly decreased infarct volume and inflammation in I/R rats. Our results suggest that BK might be a key inducer of BBB injury and B1R knockdown might provide a beneficial effect by upregulating Wnt3a.
Topics: Animals; Rats; Humans; Endothelial Cells; Receptors, Bradykinin; Bradykinin; Cytokines; Reactive Oxygen Species; Blood-Brain Barrier; Brain; Permeability; Wnt3A Protein
PubMed: 36111657
DOI: 10.1002/jbt.23213 -
Thorax Nov 1992
Review
Topics: Asthma; Bradykinin; Bronchoconstriction; Humans; Nociceptors; Respiratory Muscles
PubMed: 1465760
DOI: 10.1136/thx.47.11.979 -
Canadian Respiratory Journal 2022Two and a half years after COVID-19 was first reported in China, thousands of people are still dying from the disease every day around the world. The condition is... (Review)
Review
Two and a half years after COVID-19 was first reported in China, thousands of people are still dying from the disease every day around the world. The condition is forcing physicians to adopt new treatment strategies while emphasizing continuation of vaccination programs. The renin-angiotensin system plays an important role in the development and progression of COVID-19 patients. Nonetheless, administration of recombinant angiotensin-converting enzyme 2 has been proposed for the treatment of the disease. The catalytic activity of cellular ACE2 (cACE2) and soluble ACE2 (sACE2) prevents angiotensin II and Des-Arg-bradykinin from accumulating in the body. On the other hand, SARS-CoV-2 mainly enters cells via cACE2. Thus, inhibition of ACE2 can prevent viral entry and reduce viral replication in host cells. The benefits of bradykinin inhibitors (BKs) have been reported in some COVID-19 clinical trials. Furthermore, the effects of cyclooxygenase (COX) inhibitors on ACE2 cleavage and prevention of viral entry into host cells have been reported in COVID-19 patients. However, the administration of COX inhibitors can reduce innate immune responses and have the opposite effect. A few studies suggest benefits of low-dose radiation therapy (LDR) in treating acute respiratory distress syndrome in COVID-19 patients. Nonetheless, radiation therapy can stimulate inflammatory pathways, resulting in adverse effects on lung injury in these patients. Overall, progress is being made in treating COVID-19 patients, but questions remain about which drugs will work and when. This review summarizes studies on the effects of a recombinant ACE2, BK and COX inhibitor, and LDR in patients with COVID-19.
Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Bradykinin; COVID-19; Humans; Peptidyl-Dipeptidase A; Prostaglandin-Endoperoxide Synthases; Renin-Angiotensin System; SARS-CoV-2
PubMed: 36199292
DOI: 10.1155/2022/8698825 -
Frontiers in Immunology 2022COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology... (Observational Study)
Observational Study
COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology as it is involved in inflammation, vascular homeostasis, and coagulation. We aim to study the bradykinin cascade and its involvement in severity of patients with COVID-19. This is an observational cohort study involving 63 consecutive patients with severe COVID-19 pneumonia and 27 healthy subjects as control group. Clinical laboratory findings and plasma protein concentration of KKS peptides [bradykinin (BK), BK1-8], KKS proteins [high-molecular weight kininogen (HK)], and KKS enzymes [carboxypeptidase N subunit 1 (CPN1), kallikrein B1 (KLKB1), angiotensin converting enzyme 2 (ACE2), and C1 esterase inhibitor (C1INH)] were analyzed. We detected dysregulated KKS in patients with COVID-19, characterized by an accumulation of BK1-8 in combination with decreased levels of BK. Accumulated BK1-8 was related to severity of patients with COVID-19. A multivariate logistic regression model retained BK1-8, BK, and D-dimer as independent predictor factors to intensive care unit (ICU) admission. A Youden's optimal cutoff value of -0.352 was found for the multivariate model score with an accuracy of 92.9%. Multivariate model score-high group presented an odds ratio for ICU admission of 260.0. BK1-8 was related to inflammation, coagulation, and lymphopenia. Our data suggest that BK1-8/BK plasma concentration in combination with D-dimer levels might be retained as independent predictors for ICU admission in patients with COVID-19. Moreover, we reported KKS dysregulation in patients with COVID-19, which was related to disease severity by means of inflammation, hypercoagulation, and lymphopenia.
Topics: Bradykinin; COVID-19; Humans; Inflammation; Kallikrein-Kinin System; Lymphopenia
PubMed: 35812405
DOI: 10.3389/fimmu.2022.909342 -
British Journal of Clinical Pharmacology May 2010
Topics: Acute Disease; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans
PubMed: 20573077
DOI: 10.1111/j.1365-2125.2010.03642.x -
Revue Medicale de Liege Apr 2018The endothelium plays a vital role as part of the cardiovascular continuum. Risk factors such as hypertension and dyslipidemia unbalance angiotensin II - bradykinin... (Review)
Review
The endothelium plays a vital role as part of the cardiovascular continuum. Risk factors such as hypertension and dyslipidemia unbalance angiotensin II - bradykinin homeostasis, leading to endothelial dysfunction and changes in vascular structure that promote atherosclerosis and thrombosis. When dealing with risk factors, treatment should focus on the prevention and restoration of endothelial function. Not all cardiovascular drugs are able to reverse vascular and structural endothelial dysfunction. Increasing levels of bradykinin is an effect of the use of angiotensin-converting enzyme inhibitors (ACE-Is), and also a fundamental part of their mode of action. The cardiovascular protection observed with ACE-I, and not with sartans, can be explained rationally by the specific effects of bradykinin on the endothelium. In the pharmacological class of ACE-Is, perindopril likely produces the strongest effects on bradykinin, which may explain, at least in part, the documented superiority of this drug in the prevention and treatment of cardiovascular disease.
Topics: Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Cardiovascular Diseases; Endothelium, Vascular; Humans; Perindopril
PubMed: 29676873
DOI: No ID Found -
British Journal of Hospital Medicine... Jul 2019Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that... (Review)
Review
Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.
Topics: Bradykinin; Complement C1 Inhibitor Protein; Disease Progression; Factor XII; Hereditary Angioedema Types I and II; Humans; Kallikreins; Peptides; Quality of Life
PubMed: 31283393
DOI: 10.12968/hmed.2019.80.7.391