Observational studyCritical care (London, England)2017
Markers of nitric oxide are associated with sepsis severity: an observational study.
Observational study in Critical care (London, England), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
44 citing papers in PubMed, 78 citations in OpenAlex.
- Asymmetric dimethylarginine serum levels are associated with early mortality after allogeneic stem cell transplantation.Haematologica · 2019Trial
- Structure- and Ligand-Based Discovery of Novel Non-Arginine-Based DDAH1 Inhibitors with Anti-Triple-Negative Breast Cancer Activity.ACS medicinal chemistry letters · 2026Article
- Ulinastatin Treatment Associated with Lower Sepsis-Associated Encephalopathy Risk in Sepsis Patients: A Multicenter Observational Study.Shock (Augusta, Ga.) · 2026Observational
- Association ofInternational journal of molecular sciences · 2025Article
- Sympathetic regulation of the host immune response to bacterial sepsis.Clinical science (London, England : 1979) · 2025Review
- Lower Initial Insulin-like Growth Factor-Binding Protein-3 Concentrations May Reflect Immune Suppression and Predict Increased Risk of Sepsis-Related Mortality.International journal of molecular sciences · 2025Article
- Antimicrobial and Immunomodulatory Effects of Punicalagin and Meropenem in a Murine Model of Sublethal Sepsis.Antibiotics (Basel, Switzerland) · 2025Article
- Mechanisms of Homoarginine: Looking Beyond Clinical Outcomes.Acta physiologica (Oxford, England) · 2025Review
- Integrated analysis of stem cell-related genes shared between type 2 diabetes mellitus and sepsis.Frontiers in chemistry · 2025Article
- Immunopharmacological Insights intoCurrent pharmaceutical design · 2025Review
- Evaluation of the Diagnostic Accuracy of Exhaled Nitric Oxide as a Marker of Infection and Sepsis in Emergency Department Patients.Emergency medicine international · 2025Article
- A multicenter study of asymmetric and symmetric dimethylarginine as predictors of mortality risk in hospitalized COVID-19 patients.Scientific reports · 2024Article
- Recent advances in DDAH1 inhibitor design and discovery: insights from structure-activity relationships and X-ray crystal structures.RSC advances · 2024Review
- Methemoglobin in critically ill septic patients.Biomarkers in medicine · 2024Article
- Muramyl dipeptide potentiatesFrontiers in immunology · 2024Article
- Genes regulating oxidative-inflammatory response in circulating monocytes and neutrophils in septic syndrome.Biologia futura · 2023Article
- C-Terminal Fibronectin Exerts Beneficial Effects in Reducing Tissue Damage and Modulating Macrophage Function in a Murine Septic Model.Journal of inflammation research · 2023Article
- Divergent Dimethylarginine Dimethylaminohydrolase Isoenzyme Expression in the Central Nervous System.Cellular and molecular neurobiology · 2022Article
- Article
- A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach.Critical care (London, England) · 2022Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity.
methodThis single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression.
resultslArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) μmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) μmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) μmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) μmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA.
conclusionsIn patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.
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