Functionalized Nanogels with Endothelin-1 and Bradykinin Receptor Antagonist Peptides Decrease Inflammatory and Cartilage Degradation Markers of Osteoarthritis in a Horse Organoid Model of Cartilage.

Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation. Two vasoactive peptides, endothelin-1 and bradykinin, play important roles in OA pathogenesis. In this study, we investigated the effects of two functionalized nanogels as DDS. We assessed the effect of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and/or hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA). The biocompatibility of these nanogels, alone or in combination, was first validated on equine articular chondrocytes cultured under different oxic conditions. Further, in an OA equine organoid model via induction with interleukin-1 beta (IL-1ß), a combination of BQ-123-CHI and R-954-HA (BR5) triggered the greatest decrease in inflammatory and catabolic markers. In basal and OA conditions, BQ-123-CHI alone or in equimolar combinations with R-954-HA had weak pro-anabolic effects on collagens synthesis. These new nanogels, as part of a composite DDS, show promising attributes for treating OA.

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome.

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.

The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.

ACE-Triggered Hypertension Incites Stroke: Genetic, Molecular, and Therapeutic Aspects.

Stroke is the second largest cause of death worldwide. Angiotensin converting enzyme (ACE) gene has emerged as an important player in the pathogenesis of hypertension and consequently stroke. It encodes ACE enzyme that converts the inactive decapeptide angiotensin I to active octapeptide, angiotensin II (Ang II). Dysregulation in the expression of ACE gene, on account of genetic variants or regulation by miRNAs, alters the levels of ACE in the circulation. Variable expression of ACE affects the levels of Ang II. Ang II acts through different signal transduction pathways via various tyrosine kinases (receptor/non-receptor) and protein serine/threonine kinases, initiating a downstream cascade of molecular events. In turn these activated molecular pathways might lead to hypertension and inflammation thereby resulting in cardiovascular and cerebrovascular diseases including stroke. In order to regulate the overexpression of ACE, many ACE inhibitors and blockers have been developed, some of which are still under clinical trials.

The Incidence and Frequency of Various Causes of Angioedema in Emergency Medicine.

OBJECTIVE: Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine. METHODS: The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed. RESULTS: There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized. CONCLUSION: Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.

[Significance of kallikrein-kinin system in central nervous system diseases].

Kallikreins cleave kininogens to release kinins. Kinins exert their biological effect by activating constitutive bradykinin receptor-2 (BR2) and inducible by inflammatory cytokines bradykinin receptor-1 (BR1). Studies in animal models and some clinical observations indicate tat the activation of kallikrein - kinin system may have relevance to central nervous system (CNS) diseases, including multiple sclerosis, Alzheimer's disease, epilepsy as well as cerebral ischemia and neoplasmatic tumors. The actions of kinins include vasodilatation and increased vascular permeability may contribute to blood-brain barrier disruption. Kinins evoke pain, and stimulate of endothelial cells, white blood cells, astrocytes and microgia cells to release of prostanoids, cytokines, free radicals, nitric oxide. Kinins stimulate angiogenesis and proliferation of tumor cells. These events lead to neural tissue damage and long lasting disturbances in blood-brain barrier function. In animal models the overexpression of genes and proteins of tissue kallikrens, kininogen as well as RB1 and RB2 has been observed. Kinin receptors antagonists, especially B1R blockade decreased morphological and biochemical features of CNS inflammation. On the other hand in brain tumor models RB1 and RB2 activation has been shown to mediate reversible blood-brain barrier permeability to enhance anti-cancer drug delivery, which may have therapeutic potential.

An ABC of the Warning Signs of Hereditary Angioedema.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a genetic disorder that clinically manifests with attacks of angioedema in the subcutaneous and submucosal tissues, mainly in the extremities, abdomen, and upper airway. During attacks, vascular permeability is increased due to increased bradykinin (BK). This means that special therapies are needed for attacks that do not respond to traditional antiallergic therapies involving antihistamines, corticosteroids, and epinephrine. The recurring attacks may disable patients and lead to frequent visits to emergency rooms where misdiagnoses are common. HAE attacks may be fatal when upper-airway edema occurs, if proper treatment with a C1 inhibitor concentrate or BK receptor antagonist is not administered or an emergency tracheostomy is not performed. We propose a mnemonic method for the warning signs of HAE for the use as a diagnostic tool, i.e., the so-called "ABC" of the warning signs of HAE. The letters represent the following: A = Angioedema, B = Bradykinin, C = C1 inhibitor, D = Distress factors, E = Epinephrine nonresponsive, F = Family history, and G = Glottis/Gastrointestinal edema. To avoid fatalities, medical staff and patients, including family members, must be aware of HAE. An alphabetical mnemonic method has been developed and we hope it may benefit patients.

Emerging Targets for the Management of Osteoarthritis Pain.

Worldwide, osteoarthritis (OA) is one of the leading causes of chronic pain, for which adequate relief is not available. Ongoing peripheral input from the affected joint is a major factor in OA-associated pain. Therefore, this review focuses predominantly on peripheral targets emerging in the preclinical and clinical arena. Nerve growth factor is the most advanced of these targets, and its blockade has shown tremendous promise in clinical trials in knee OA. A number of different types of ion channels, including voltage-gated sodium channels and calcium channels, transient receptor potential channels, and acid-sensing ion channels, are important for neuronal excitability and play a role in pain genesis. Few channel blockers have been tested in preclinical models of OA, with varying results. Finally, we discuss some examples of G-protein coupled receptors, which may offer attractive therapeutic strategies for OA pain, including receptors for bradykinin, calcitonin gene-related peptide, and chemokines. Since many of the pathways described above can be selectively and potently targeted, they offer an exciting opportunity for pain management in OA, either systemically or locally.

Role of selective blocking of bradykinin receptor subtypes in attenuating allergic airway inflammation in guinea pigs.

The present study was designed to evaluate the potential role of bradykinin antagonists (R-715; bradykinin B1 receptor antagonist and icatibant; bradykinin B2 receptor antagonist) in treatment of allergic airway inflammation in comparison to dexamethasone and montelukast. R-715 as dexamethasone significantly decreased peribronchial leukocyte infiltration, bronchoalveolar lavage fluid (BALF) albumin and interleukin 1ß as well as serum OVA-specific IgE level. Also, R-715 like montelukast significantly decreased BALF cell count (total and eosinophils). Icatibant showed negative results. The current findings suggest that selective bradykinin B1 receptor antagonists may have the therapeutic potential for the treatment of allergic airway inflammation.

A Decade of Change: Recent Developments in Pharmacotherapy of Hereditary Angioedema (HAE).

Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare but medically significant disease that can be associated with considerable morbidity and mortality. Research into the pathogenesis of HAE-C1-INH has expanded greatly in the last six decades and has led to new clinical trials with novel therapeutic agents and treatment strategies. Mechanisms of pharmacotherapy include (a) supplementing C1-INH, the missing serine-protease inhibitor in HAE; (b) inhibiting the activation of the contact system and the uncontrolled release of proteases in the kallikrein-kinin system, by blocking the production/function of its components; (c) inhibiting the fibrinolytic system by blocking the production/function of its components; and (d) inhibiting the function of bradykinin at the endothelial level. Strategies for managing HAE-C1-INH are aimed at treating acute attacks, or preventing attacks, through the use of prophylactic treatment. Available agents for treating acute attacks include plasma-derived C1-INH concentrates, a recombinant C1-INH, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor. Long-term prophylactic treatments include attenuated androgens, plasma-derived C1-INH concentrates, and anti-fibrinolytics. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are already approved for self-administration at home. The number of management options for HAE-C1-INH has increased considerably within the past decade, thus helping to alleviate the burden of this rare disease.

Life-threatening ACE inhibitor-induced angio-oedema successfully treated with icatibant: a bradykinin receptor antagonist.

We present a case of a 75-year-old woman treated with an ACE inhibitor, who presented with angio-oedema of the tongue and had difficulty speaking. No symptoms of anaphylaxis or urticaria were present. The patient was treated intravenously with antihistamine and glucocorticoid in combination with adrenaline inhalations. After 6 h in the hospital the swelling progressed, and the patient was admitted to the intensive care unit and treated with one injection of icatibant-a bradykinin receptor antagonist. The patient reported subjective relief after 20-30 min and the swelling resolved within 2 h. Although the angio-oedema was potentially life threatening, the patient avoided intubation and mechanical ventilation. ACE inhibitor-induced angio-oedema is most likely caused by an accumulation of bradykinin and substance P. Consequently, a bradykinin receptor antagonist is the rational treatment of choice instead of antiallergic medications, which have no proven efficacy in this condition.

Angiotensin-converting enzyme inhibitor-induced angioedema--a dangerous new epidemic.

Angioedema is a sudden localised and often asymmetric swelling of the skin or mucous membranes caused by transient increased endothelial permeability causing plasma extravasation. In the last decades the incidence of severe angioedema involving the upper airways and even fatal outcome due to asphyxia has increased. This is mainly due to pharmaceuticals such as angiotensin converting enzyme-inhibitors, which are extensively used worldwide. Some aspects of the pathophysiology have been elucidated and the vasoactive molecule bradykinin is shown to be one of the main causative agents. The diagnosis is often delayed and traditional treatment usually ineffective. Complement C1 inhibitor concentrate and bradykinin receptor antagonists, normally used to treat patients with hereditary angioedema, have shown good results when used in patients with bradykinin-mediated angioedema. This review discusses the disease, prognosis and treatment options.