The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
- Conditions
- Sepsis, Endotoxemia, Immunosuppression
- Interventions
- Drug: PlaceboDrug: LPS
- Registration Number
- NCT05570643
- Lead Sponsor
- Radboud University Medical Center
- Brief Summary
We will investigate whether human endotoxemia induces changes in human bone marrow cells and their downstream effector cells. To comprehensively investigate underlying mechanisms behind functional and transcriptional changes in these cell types, we will use state-of-the-art systems biology techniques, including single cell transcriptomics (epi)genetics, and metabolomics.
- Detailed Description
In the present study, we want to further elucidate the mechanisms behind systemic inflammation and endotoxin tolerance in vivo in humans by focusing on functional changes in hematopoietic stem and progenitor cells. Healthy male volunteers will be challenged with endotoxin to evoke a transient systemic inflammatory response. To evaluate the responses over time, blood and bone marrow aspirates will be collected at multiple timepoints. To comprehensively investigate underlying mechanisms behind functional changes, we will use state-of-the-art systems biology techniques, including single cell transcriptomics, epigenetics (e..g. scATACseq), and metabolomic. As such, this study will yield a comprehensive insight into inflammatory signaling in the different compartments of the body and will thereby improve our understanding of systemic inflammation, endotoxin tolerance,and sepsis, possibly revealing new therapeutic targets to improve sepsis outcome.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 12
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy (as confirmed by medical history, examination, ECG, blood sampling)
- Use of any medication
- Smoking
- History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema)
- Known anaphylaxis or hypersensitivity to the non-investigational products or their excipients.
- History or signs of hematological disease (bone marrow dysfunction):
- Thrombocytopenia (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L)
- Abnormalities in leukocyte differential counts
- History, signs or symptoms of cardiovascular disease, in particular:
- Previous spontaneous vagal collapse
- History of atrial or ventricular arrhythmia
- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
- Renal impairment (defined as plasma creatinine >120 μmol/l)
- Liver enzyme abnormalities (above 2x the upper limit of normal)
- Medical history of any disease associated with immune deficiency
- CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L, or clinically significant acute illness, including infections, within 3 weeks before labeling day
- Previous (participation in a study with) LPS administration
- Any vaccination within 3 months prior to labeling day
- Participation in a drug trial or donation of blood 3 months prior to labeling day
- Recent hospital admission or surgery with general anesthesia (<3 months to labeling day)
- Use of recreational drugs within 21 days prior to labeling day
- Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo group Placebo Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%). LPS group LPS Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.
- Primary Outcome Measures
Name Time Method Change in function and transcriptional pathways 15 days The change in function and transcriptional pathways (gene expression) of hematopoietic progenitor cells and blood leukocytes (using various functional assays and single cell RNAseq) following human endotoxemia.
- Secondary Outcome Measures
Name Time Method Change in (Genome-wide) chromatin accessibility 15 days The change in epigenomic profile (chromatin accessibility) of hematopoietic progenitor cells and blood leukocytes (using single cell ATACseq) following human endotoxemia.
Change in cellular metabolism 15 days The change in cellular metabolism of hematopoietic progenitor cells and blood leukocytes (e.g. using Seahorse analyzer, CYTOF) following human endotoxemia.
Life-span of blood leukocytes during endotoxemia 8 days To determine the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans during human endotoxemia (using Deuterium labeling).
Change in macrophage activity in the brain 15 days To changes in tissue resident macrophages activity in the brain (assessed using 18F-DPA-714 labeling and PET examinations) following human endotoxemia.
Life-span of blood leukocytes during homeostasis 8 days To assessment of the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans at homeostasis (using Deuterium labeling).
Trial Locations
- Locations (1)
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
🇳🇱Nijmegen, Gelderland, Netherlands