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Proinflammatory Peptides in Relation to Other Inflammatory Mediators
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Pierangelo Geppetti, Costanza Emanueli, Michela Figini, Domenico Regoli
The kinins, bradykinin, kallidin, and des Arg9-bradykinin, are formed through enzymatic cleavage of their precursors, the kininogens, by various proteases, termed kallikreins (55). Kinins are activated by different stimuli, including injury, inflammation, and low pH. Kinins mediate their biological effects by activating B1 and B2 receptors (56). Chapters 10 and 20 in this book describe in detail the pharmacological and pathophysiological aspects of kinins. Kinins are powerful algesic agents and cause all the main signs of inflammation. In the airways, kinins increase vascular permeability and blood flow, and cause secretion from seromucous glands and bronchoconstriction. There is evidence that kinins produce these effects by activating B2 receptors on effector cells directly. Kinins may also stimulate a variety of cells to release diverse mediators that markedly enhance, or sometimes limit, their own inflammatory action. One of the main proinflammatory pathways by which kinins cause inflammation is stimulation of sensory nerves and release of sensory neuropep-tides. Pharmacological studies in which bradykinin was applied locally to the airways showed that plasma extravasation and bronchoconstriction were mediated by tachykinin release from sensory nerves (57,58).
Sensory and Inflammatory Peptide Receptors in Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Plasma proteins give rise to peptide mediators in addition to kinins. Activations of the complement cascade gives rise to two components, C3a and C5a, which are termed anaphylatoxins and which have airway effects.101
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The onset of tissue swelling and pain is probably mediated by kinins and prostaglandins. The effect of salicylates (aspirin) in reducing these symptoms is probably related to their ability to inactivate kinins by preventing the activation of kallikrein. These drugs may exert part of their anti-inflammatory effect by rendering lysosomal membranes more stable and less permeable, thus blocking the release of proteolytic enzymes and hydrolases. Salicylates do not affect bradykinin synthesis or inhibit the formation of kallikrein nor do they antagonize histamine or serotonin. The antirheumatic effect of salicylates is related to the inflammatory component of this disease,511 suppressing the clinical signs, and in some cases even improving the histological picture. Subsequent damage, cardiac lesions, and other visceral changes are unaffected by salicylates. The mechanism of action of aspirin is related to the inhibition of prostaglandin synthesis (Figure 28), and the anti-inflammatory effect of adrenocortical steroids is associated with the stabilization of lysosomal membranes.
Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency
Published in Expert Opinion on Emerging Drugs, 2022
Andrea Zanichelli, Vincenzo Montinaro, Massimo Triggiani, Francesco Arcoleo, Debora Visigalli, Mauro Cancian
The first discovery of the deficient protein responsible for HAE, i.e. C1-inhibitor, dates back to 1963 [3,4]. Shortly thereafter, supplementation of plasma-derived C1-inhibitor (pdC1-INH) became the first therapeutic option for acute attacks of HAE [3,4]. Attenuated androgens, such as danazol and stanozolol, and antifibrinolytics, such as Ɛ-aminocaproic acid and tranexamic acid, were initially used for prophylaxis. In the ’90s, during the biotech era of drug designing, the underlying pathogenetic mechanism of HAE was discovered. It involves the contact-kinin systems activation and results in the generation of bradykinin, which is the mediator of increased vascular permeability. These findings are likely responsible for the development and subsequent availability on the market of several therapies, despite the rarity of the disease [3,4]. The number of new treatment options to target specific molecules involved in the genesis of angioedema, i.e. factor XIIa, C1-INH, prekallikrein, kallikrein, bradykinin, and bradykinin type 2 receptor, has been substantially increasing over the last decade. Novel mechanisms of action include RNA-targeted antisense against prekallikrein, RNA interference drugs against factor XII, and gene therapy.
Macroglossia secondary to lisinopril-induced acute angioedema
Published in Baylor University Medical Center Proceedings, 2019
Colten Ducote, Matthew J. Kesterke, Ritesh Bhattacharjee, Andrew Read-Fuller, Likith V. Reddy
Macroglossia is a clinical condition resulting in enlargement of the tongue beyond the anterior teeth.1 The condition is caused by vascular anomalies, allergic reactions,2,3 or congenital conditions.4–8 Angiotensin-converting enzyme inhibitors (ACEIs) are the most common medication causing angioedema.9,10 Studies found that the incidence of ACEI angioedema is higher in older adults, patients with chronic heart failure, and African American women.11 ACEIs also inhibit the kallikrein-kinin system from degrading bradykinin, leading to increased vasodilation.12,13 Angioedema can cause significant swelling, resulting in acute airway obstruction and eventual death.5,12,14 Partial glossectomy is a valid treatment option for macroglossia that does not resolve with medication.5,7 This case report documents the diagnoses and surgical treatment of two cases of ACEI-induced angioedema and macroglossia treated at Baylor University Medical Center (BUMC) at Dallas.
Inhibition of plasma kallikrein–kinin system to alleviate renal injury and arthritis symptoms in rats with adjuvant-induced arthritis
Published in Immunopharmacology and Immunotoxicology, 2018
Jie Zhu, Hui Wang, Jingyu Chen, Wei Wei
The plasma KKS plays a critical role in physiology4. Evidence suggests the plasma KKS is not only closely related to the adaptive immune response, but also has a relationship with native immune response11. The precursors of kinin are widely distributed in blood and tissues. Kinin receptor profile may change in a variety of pathological conditions, including autoimmune diseases27. As a potential drug target, the plasma KKS was received considerable attentions14. The present investigation was to explore the role of plasma KKS in kidney injury of RA through a rat model of AA. We found that the arthritis index was significantly increased in AA rats after injection with FCA. Inflammatory cell infiltration, degenerations of tubular epithelial cell vacuole, podocytes and mitochondria vacuolar in kidney tissue were found. The pathological and ultrastructural changes of kidney suggest that kidney damage was accompanied in AA rats. Simultaneously, the results of high levels of Cr and BUN also confirm kidney damage and dysfunction in AA rats. Additional, the results of high expressions of NGAL and Kim-1 further illustrate kidney damage in AA rats.