A zinc metallopeptidase neurolysin (Nln) processes diverse bioactive peptides to regulate signaling in the mammalian nervous system. To understand how Nln interacts with various peptides with dissimilar sequences, we determined crystal structures of Nln in complex with diverse peptides including dynorphins, angiotensin, neurotensin, and bradykinin. The structures show that Nln binds these peptides in a large dumbbell-shaped interior cavity constricted at the active site, making minimal structural changes to accommodate different peptide sequences. The structures also show that Nln readily binds similar peptides with distinct registers, which can determine whether the peptide serves as a substrate or a competitive inhibitor. We analyzed the activities and binding of Nln toward various forms of dynorphin A peptides, which highlights the promiscuous nature of peptide binding and shows how dynorphin A (1-13) potently inhibits the Nln activity while dynorphin A (1-8) is efficiently cleaved. Our work provides insights into the broad substrate specificity of Nln and may aid in the future design of small molecule modulators for Nln.

Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin\'s role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin\'s role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.

Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days.

The renin-angiotensin system (RAS) is known to affect diverse physiological processes that affect the functioning of many key organs. Angiotensin-converting enzyme (ACE) modulates a variety of bioactive peptides associated with pain. ACE inhibitors (ACEis) have found applications in the treatment of cardiovascular, kidney, neurological and metabolic disorders. However, ACEis also tend to display undesirable effects, resulting in increased pain sensitization and mechanical allodynia. In this review, we provide comprehensive discussion of preclinical and clinical studies involving the evaluation of various clinically approved ACEis. With the emerging knowledge of additional factors involved in RAS signaling and the indistinct pharmacological role of ACE substrates in pain, extensive studies are still required to elucidate the mechanistic role of ACE in pain perception.

Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.

Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section \"3.5 IV alteplase\" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes.

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.

The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.

A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.

The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared with mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared with mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced prosecretory responses to the nonselective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.NEW & NOTEWORTHY This is the first study to characterize the intestinal function of naked mole-rats. We found that these animals show a robust gut tissue structure, displaying thicker intestinal layers, longer villi, and larger crypts. Naked mole-rats showed more and larger goblet cells, with increased mucus content. Intestinal permeability, especially in the ileum, was substantially lower than that of mice. Finally, naked mole-rats showed reduced intestinal anion secretion in response to serotonin, bradykinin, histamine, capsaicin, and forskolin.