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Nitric oxide inhalation and glucocorticoids as combined treatment in human experimental endotoxemia
Karolinska University Hospital.ORCID iD: 0000-0002-3287-6504
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2008 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 36, no 11, p. 3043-3047Article in journal (Refereed) Published
Abstract [en]

Objective: 

Inhaled nitric oxide and glucocorticoids as a combination therapy may attenuate endotoxin-induced inflammatory responses in humans as indicated by levels of cytokines and clinical signs. Since other authors have shown that combined inhaled nitric oxide and steroids improved the histologic damage both in pulmonary and systemic organs in a porcine endotoxin model, we examined if an anti-inflammatory interaction could be demonstrated in humans.

Design: 

Double-blind, crossover, placebo-controlled randomized study.

Setting: 

The intensive care unit in a university hospital.

Subjects: 

Fifteen healthy white volunteers (4 women, 11 men).

Interventions: 

Endotoxin (2 ng/kg) was administered intravenously. Thirty minutes thereafter the volunteers were given glucocorticoids (2 mg/kg) intravenously and inhaled nitric oxide 30 ppm or placebo (nitrogen) administered through a nasal cannula. Blood samples and clinical signs were collected before and up to 5.5 hrs after the endotoxin infusion.

Measurements and Main Result: 

Following endotoxin body temperature and heart rate increased significantly compared with baseline. There were no differences observed between the treatments. Endotoxin challenge also markedly elevated the plasma levels of tumor necrosis factor-α, interleukin (IL)-6, IL-10, and IL1-ra concentrations during the study period. No difference between placebo/glucocorticoids and inhaled nitric oxide/glucocorticoids treatment was seen in the cytokine response.

Conclusions: 

In a human experimental inflammatory model using endotoxin, inhaled nitric oxide and glucocorticoids in low doses given after the endotoxin challenge did not modify the inflammatory cascade as monitored in this study.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2008. Vol. 36, no 11, p. 3043-3047
Keywords [en]
cytokines, inflammation, nitric oxide, receptor for advanced glycation end products, sepsis, volunteers
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-540360DOI: 10.1097/ccm.0b013e318186f5b2ISI: 000260694200013OAI: oai:DiVA.org:uu-540360DiVA, id: diva2:1905649
Available from: 2024-10-14 Created: 2024-10-14 Last updated: 2024-10-15Bibliographically approved
In thesis
1. Immune response in a human endotoxin model and critical COVID-19
Open this publication in new window or tab >>Immune response in a human endotoxin model and critical COVID-19
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Sepsis arises, by definition, from a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in antimicrobial treatments and organ support, pharmacological breakthroughs remain limited. The human endotoxin model serves as a bridge between animal models and human trials, simulating systemic inflammatory response syndrome (SIRS) and sepsis for evaluating potential therapies. 

The COVID-19 pandemic, driven by SARS-CoV-2, caused widespread morbidity and mortality. Patients with severe disease exhibited immune dysregulation, characterized by hyperinflammation and immune suppression. Given the similarity in immune dysregulation, insights from previous SARS outbreaks and sepsis research were applied to the SARS-CoV-2, emphasizing the need to balance immune suppression and infection-fighting capacity in both conditions.

Methods: Part one involved a human endotoxemia model, where endotoxin was administered to healthy volunteers, to simulate systemic inflammatory response syndrome (SIRS). Inhaled nitric oxide (iNO) and glucocorticoid (GC) co-administration was assessed for immune modulation based on previous results from a porcine model. 

Part two focused on COVID-19 patients in the PRONMED cohort with severe disease admitted to the ICU, investigating longitudinal immune cells and biomarker levels. In addition potential sex-based differences in inflammatory profiles were evaluated.

Results: In the human endotoxemia model, iNO/GC failed to modify the immune response, despite promising results in a porcine study. Differences in species-specific responses and endotoxin dosing likely contributed to these outcomes. 

Among COVID-19 patients, elevated pro-inflammatory cytokines (TNFα, IL-6, IL-8), neutrophil activation, marked lymphopenia with attenuated expressions of lymphokines receptors were observed. In addition a dynamic aberrant expression of CD-markers was observed on neutrophils. 

Men had an overall heightened immune response compared to women, except for cytokines for Th1 response, where no difference was found.

Conclusions: The failure of iNO/GC to replicate animal results highlights challenges in translating findings across species.

In COVID-19 patients, significant immune dysregulation was observed. Tailored interventions—with precise patient selection, optimized timing and dosing, and potential influences from sex hormones—are likely key to improving outcomes and minimizing harm in sepsis patients. Additionally, further research is crucial to better understand the role of neutrophils in the adaptive immune response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2092
Keywords
Human endotoxin model, SIRS, inhaled nitric oxide, glucocorticoids, Sepsis, inflammation, COVID-19, lymphocytes, neutrophils, sex differences
National Category
Medical and Health Sciences
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-540368 (URN)978-91-513-2269-8 (ISBN)
Public defence
2024-12-02, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 08:00 (Swedish)
Opponent
Supervisors
Available from: 2024-11-08 Created: 2024-10-15 Last updated: 2024-11-11

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