States of quinolinic acid excess in urine: A systematic review of human studies

IntroductionQuinolinic acid is an intermediate compound derived from the metabolism of dietary tryptophan. Its accumulation has been reported in patients suffering a broad spectrum of diseases and conditions. In this manuscript, we present the results of a systematic review of research studies assessing urinary quinolinic acid in health and disease.MethodsWe performed a literature review using PubMed, Cochrane, and Scopus databases of all studies reporting data on urinary quinolinic acid in human subjects from December 1949 to January 2022.ResultsFifty-seven articles met the inclusion criteria. In most of the reported studies, compared to the control group, quinolinic acid was shown to be at increased concentration in urine of patients suffering from different diseases and conditions. This metabolite was also demonstrated to correlate with the severity of certain diseases including juvenile idiopathic inflammatory myopathies, graft vs. host disease, autism spectrum disorder, and prostate cancer. In critically ill patients, elevated quinolinic acid in urine predicted a spectrum of adverse outcomes including hospital mortality.ConclusionQuinolinic acid has been implicated in the pathophysiology of multiple conditions. Its urinary accumulation appears to be a feature of acute physiological stress and several chronic diseases. The exact significance of these findings is still under investigation, and further studies are needed to reveal the subsequent implications of this accumulation

PAR1 Agonists Stimulate APC-Like Endothelial Cytoprotection and Confer Resistance to Thromboinflammatory Injury

Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed “parmodulins” that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB–mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling

Inflammatory Markers of the Systemic Capillary Leak Syndrome (Clarkson Disease)

Objectives: The Systemic Capillary Leak Syndrome (SCLS) is a rare and potentially fatal disorder resembling systemic anaphylaxis that is characterized by transient episodes of hypotensive shock and peripheral edema. The pathogenesis of SCLS is unknown, and triggers for attacks are apparent only in a minority of patients. We introduce a clinical algorithm for the diagnosis of SCLS, and we investigated potential serum biomarkers of acute SCLS episodes. Methods: We analyzed serum cytokines in a cohort of 35 patients with an established diagnosis of SCLS and characterized the effects of SCLS sera on endothelial cell function. We investigated the cellular source(s) of CXCL10, a chemokine that was significantly elevated in both basal and acute SCLS sera, by flow cytometry. Results: Several cytokines were elevated in acute SCLS sera compared to baseline or sera from healthy controls, including CXCL10, CCL2, IL-1β, IL-6, IL-8, IL-12 and TNFα. The majority of acute sera failed to activate endothelial cells as assessed by surface adhesion marker expression. Monocytes appear to be the major source of serum CXCL10, and the percentage of CXLC10+ monocytes in response to IFNγ stimulation was increased in SCLS subjects compared to controls. Conclusions: The presence of proinflammatory cytokines in acute SCLS sera suggests that inflammation or infection may have a role in triggering episodes. The enhanced capacity of monocytes from SCLS patients to produce CXCL10 suggests a new therapeutic avenue for SCLS

Neutrophil activation in systemic capillary leak syndrome (Clarkson disease)

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer‐based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro‐inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak

Angiopoietin-1 Requires Oxidant Signaling through p47phox to Promote Endothelial Barrier Defense

Background: Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidase (NOX) signaling. Methods and Findings: Using primary human microvascular endothelial cells (HMVECs), we found that Angpt-1 stimulation induces phosphorylation of p47phox and a brief oxidative burst that is lost when chemical inhibitors of NOX activity or siRNA against the NOX component p47phox were applied. As a result, there was attenuated ROS activity, disrupted junctional contacts, enhanced actin stress fiber accumulation, and induced gap formation between confluent HMVECs. All of these changes were associated with weakened barrier function. The ability of Angpt-1 to prevent identical changes induced by inflammatory permeability mediators, thrombin and lipopolysaccharides (LPS), was abrogated by p47phox knockdown. P47phox was required for Angpt-1 to activate Rac1 and inhibit mediator-induced activation of the small GTPase RhoA. Finally, Angpt-1 gene transfer prevented vascular leakage in wildtype mice exposed to systemically administered LPS, but not in p47phox knock out (p47−/−) littermates. Conclusions: These results suggest an essential role for NOX signaling in Angpt-1-mediated endothelial barrier defense against mediators of systemic inflammation. More broadly, oxidants generated for signal transduction may have a barrier-promoting role in vascular endothelium

Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature. METHODS AND FINDINGS: We describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice. CONCLUSIONS: Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function

The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis

Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept

Membrane paradigm realized?

Are there any degrees of freedom on the black hole horizon? Using the `membrane paradigm' we can reproduce coarse-grained physics outside the hole by assuming a fictitious membrane just outside the horizon. But to solve the information puzzle we need `real' degrees of freedom at the horizon, which can modify Hawking's evolution of quantum modes. We argue that recent results on gravitational microstates imply a set of real degrees of freedom just outside the horizon; the state of the hole is a linear combination of rapidly oscillating gravitational solutions with support concentrated just outside the horizon radius. The collective behavior of these microstate solutions may give a realization of the membrane paradigm, with the fictitious membrane now replaced by real, explicit degrees of freedom.Comment: 8 pages, Latex, 3 figures (Essay given second place in Gravity Research Foundation essay competition 2010

Beta-adrenergic antagonist tolerance in amyloid cardiomyopathy

Background: Beta-adrenergic antagonists or blockers (BB) are a cornerstone of cardiac therapy for multiple indications. However, BB are considered relatively contraindicated in amyloid cardiomyopathy due to poor tolerance. This intolerance is hypothesized to be due to concomitant neuropathy and significant restrictive cardiomyopathy. This study analyzes the incidence and characteristics of BB tolerance in patients with amyloid cardiomyopathy. Methods: Through a single-center retrospective chart review, patients with amyloid cardiomyopathy, confirmed by endomyocardial biopsy or technetium-99 pyrophosphate scan, were identified and clinical data was collected. Statistical methods included Chi-square test and two sample Results: Of 135 cardiac amyloidosis patients, 27 patients (20.0%) had no BB use, 56 patients (41.5%) were current BB users, and 52 patients (38.5%) were prior BB users. The most frequent indications for BB use were heart failure, hypertension, coronary artery disease, and arrhythmia. The most common reason for stopping BB therapy was hypotension (62.8%) followed by fatigue, bradycardia, and orthostasis. Neurologic symptoms at the initial BB prescription or most recent evaluation were not significantly different between current and prior BB users. Their cardiovascular profiles were similar by ejection fraction, wall thickness, troponin I, and brain natriuretic peptide. There was no association for BB discontinuation based on amyloid subtype, sex, or race. Conclusion: The majority of patients with amyloid cardiomyopathy were prescribed BB, and over half of these patients still tolerated BB therapy. Current and prior BB users had similar profiles from a cardiovascular and neurologic perspective, with no association identified to predict BB discontinuation