Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine.

Vertical sleeve gastrectomy associates with airway hyperresponsiveness in a murine model of allergic airway disease and obesity.

Introduction: Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization.

Stakeholder-Guided Development of Dialysis Vascular Access Education Materials.

Background: Initiating hemodialysis an arteriovenous (AV) access is considered best practice for most patients. Despite the well-recognized advantages of AV access, 80% of US patients start hemodialysis with a catheter. Limited patient knowledge about vascular access, among other factors, may play a role in this high rate.

A deep learning approach to student registered nurse anesthetist (SRNA) education.

Objectives: This manuscript describes the application of deep learning to physiology education of Student Registered Nurse Anesthetists (SRNA) and the benefits thereof. A strong foundation in physiology and the ability to apply this knowledge to challenging clinical situations is crucial to the successful SRNA. Deep learning, a well-studied pedagogical technique, facilitates development and long-term retention of a mental knowledge framework that can be applied to complex problems.

Dialysis Access: At the Intersection of Policy, Innovation, and Clinical Care.

The Advancing American Kidney Health executive order aims to reduce the incidence of end-stage kidney disease, promote home dialysis therapies, increase the number of kidney transplants, and encourage innovation in new technologies, evidence-based practice, and early detection of kidney disease. Improvements in dialysis access care are essential to the success and expansion of this program, and to being able to provide high-quality, cost-efficient care to this patient population. Specifically, the need for expanded access to home dialysis will require surgeons and interventionalists to become proficient and trained in peritoneal dialysis catheter placement and for the referral process to be streamlined to accommodate the increased interest in this modality.

Methods to Investigate the Roles for β-Arrestin-2 in Allergic Inflammatory Airway Disease.

Spatial and temporal control of gene expression using cre/loxP technology is a major methodological advance for biomedical research. The ability to alter gene expression after an in vivo disease model has been established and allows researchers the opportunity to examine the impact of that gene on the perpetuation of a disease, a mechanistic insight that is arguably more therapeutically relevant than developmental mechanisms.We used the cre/LoxP technology in mice to show that β-arrestin-2, a gene previously shown to be required for the development of the asthma phenotype, is also required for the perpetuation of, at least, the airway hyperresponsiveness characteristic of that phenotype.

Therapeutic Potential of Targeting ß-Arrestin.

ß-arrestins are multifunctional proteins that modulate heptahelical 7 transmembrane receptors, also known as G protein-coupled receptors (GPCRs), a superfamily of receptors that regulate most physiological processes. ß-arrestin modulation of GPCR function includes termination of G protein-dependent signaling, initiation of ß-arrestin-dependent signaling, receptor trafficking to degradative or recycling pathways, receptor transactivation, transcriptional regulation, and localization of second messenger regulators. The pleiotropic influence ß-arrestins exert on these receptors regulates a breadth of physiological functions, and additionally, ß-arrestins are involved in the pathophysiology of numerous and wide-ranging diseases, making them prime therapeutic targets.

Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.

Arrestins have been shown to regulate numerous G protein-coupled receptors (GPCRs) in studies employing receptor/arrestin overexpression in artificial cell systems. Which arrestin isoforms regulate which GPCRs in primary cell types is poorly understood. We sought to determine the effect of β-arrestin-1 or β-arrestin-2 inhibition or gene ablation on signaling and function of multiple GPCRs endogenously expressed in airway smooth muscle (ASM).

Quantification of beta adrenergic receptor subtypes in beta-arrestin knockout mouse airways.

In allergic asthma Beta 2 adrenergic receptors (β2ARs) are important mediators of bronchorelaxation and, paradoxically, asthma development. This contradiction is likely due to the activation of dual signaling pathways that are downstream of G proteins or β-arrestins. Our group has recently shown that β-arrestin-2 acts in its classical role to desensitize and constrain β2AR-induced relaxation of both human and murine airway smooth muscle.

Hydrogen sulfide acts as a pro-inflammatory mediator in rheumatic disease.

Objective: Hydrogen sulfide (H S) is a gaseous mediator produced in the body. In experimental models, endogenously produced H S has been shown to have pro-inflammatory effects. The aim of this study was to investigate whether H S is present in three common rheumatic diseases, rheumatoid arthritis (RA), gout and osteoarthritis (OA) and to determine if H S levels correlate with disease activity.

The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse.

Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-γ-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis.

β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.

Proteinase-Activated receptor-2 (PAR(2)), a G-protein-coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR(2) have been proposed for treating asthma. PAR(2) can signal through two independent pathways: a β-arrestin-dependent one that promotes leukocyte migration, and a G-protein/Ca(2+) one that is required for prostaglandin E(2) (PGE(2)) production and bronchiolar smooth muscle relaxation.

Effects of S-propargyl-cysteine (SPRC) in caerulein-induced acute pancreatitis in mice.

Hydrogen sulfide (H(2)S), a novel gaseous messenger, is synthesized endogenously from L-cysteine by two pyridoxal-5'-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). S-propargyl-cysteine (SPRC) is a slow H(2)S releasing drug that provides cysteine, a substrate of CSE. The present study was aimed to investigate the effects of SPRC in an in vivo model of acute pancreatitis (AP) in mice.

Hydrogen sulfide in inflammation: friend or foe?

Hydrogen sulfide (H(2)S), the gaseous mediator produced by various cells in our body, was recently discovered to play a major role in human physiology despite its toxic nature known for centuries. In addition to its pathophysiological relevance in cardiovascular and neuronal disorders, there is considerable interest in the significance of H(2)S in inflammation. A number of preclinical studies in our laboratory as well as by others, using H(2)S donors and inhibitors of its endogenous synthesis, have provided evidence for both pro- and anti-inflammatory character of H(2)S.

Neurokinin-1 receptor antagonist treatment in polymicrobial sepsis: molecular insights.

Neurokinin-1 receptor blocking has been shown to be beneficial against lung injury in polymicrobial sepsis. In this paper, we evaluated the possible mediators and the mechanism involved. Mice were subjected to cecal ligation and puncture (CLP-) induced sepsis or sham surgery.

Substance P in polymicrobial sepsis: molecular fingerprint of lung injury in preprotachykinin-A-/- mice.

Deletion of mouse preprotachykinin-A (PPTA), which encodes mainly for neuropeptide substance P, has been shown to protect against lung injury and mortality in sepsis. This study explored microarray-based differential gene expression profiles in mouse lung tissue 8 h after inducing microbial sepsis and the effect of PPTA gene deletion. A range of genes differentially expressed (more than two-fold) in microarray analysis was assessed, comparing wild-type and PPTA-knockout septic mice with their respective sham controls, and the data were further validated.

Plasma cytokine profiles in preprotachykinin-A knockout mice subjected to polymicrobial sepsis.

During the course of polymicrobial sepsis, a range of pro- and antiinflammatory cytokines are produced by the host immune system. Successful recovery from sepsis involves striking a balance between these counteracting cytokines. We herein investigated the circulating cytokine profiles in preprotachykinin-A knockout (PPTA(-/-)) mice, which have been found to be protected significantly against microbial sepsis, by employing multiplexed bead-based suspension arrays for the measurement of 18 plasma cytokines.

Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats.

Objectives: The effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats.

Methods: A single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8-day oral regimen of rutin, 1 g/kg daily.

Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia.

Endotoxemia is a life-threatening, inflammatory condition that involves multiple organ injury and dysfunction. Preprotachykinin-A (PPT-A) gene products, substance P (SP), and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products on multiple organ injury in LPS-induced endotoxemia, endotoxemia was induced by LPS administration (10 mg/kg, i.

Hydrogen sulfide up-regulates substance P in polymicrobial sepsis-associated lung injury.

Hydrogen sulfide (H2S) has been shown to induce the activation of neurogenic inflammation especially in normal airways and urinary bladder. However, whether endogenous H2S would regulate sepsis-associated lung inflammation via substance P (SP) and its receptors remains unknown. Therefore, the aim of the study was to investigate the effect of H2S on the pulmonary level of SP in cecal ligation and puncture (CLP)-induced sepsis and its relevance to lung injury.

Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis.

Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP).

Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury.

Acute pancreatitis is a common, and as yet incurable, clinical condition, the incidence of which has been increasing over recent years. Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that treatment with a neutralizing antibody against CINC, a CXC chemokine, protects rats against acute pancreatitis-associated lung injury.

Preprotachykinin-A gene products are key mediators of lung injury in polymicrobial sepsis.

Preprotachykinin-A (PPT-A) gene products substance P and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products in lung injury in sepsis, polymicrobial sepsis was induced by cecal ligation and puncture in PPT-A gene-deficient mice (PPT-A(-/-)) and the wild-type control mice (PPT-A(+/+)). PPT-A gene deletion significantly protected against mortality, delayed the onset of lethality, and improved the long-term survival following cecal ligation and puncture-induced sepsis.