Effects of Oxygen Status on Hypoxia Inducible Factor 1-α and Inflammation. A Pilot Proof of Principle Study.

Phase 1

Completed

• Conditions: Hypoxia; Hyperoxia
• Interventions: Other: Hypoxia; Other: Hyperoxia

• Registration Number: NCT01889823
• Lead Sponsor: Radboud University Medical Center

Brief Summary

It has been shown in in vitro and animal models that hypoxia can have pro-inflammatory effects and hyperoxia can have anti-inflammatory effects. The pro-inflammatory effect could be the result of activation of Hypoxia Inducible Factor, a transcription factor that is known to activate many cell systems aimed at cell survival, including the inflammatory response. The anti-inflammatory effects of hyperoxia could be the annihilation of Hypoxia Inducible Factor, but also a decrease in inflammation due to oxygen toxicity resulting in a decrease in clearance of pathogens. These effects have been sparsely studied in humans. Therefore, we hypothesize that hypoxia results in an increase in Hypoxia Inducible Factor in circulating leukocytes and increases inflammatory reactions, whereas hyperoxia decreases these reactions.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-06
• Study First Submitted: 2013-06-26
• Study First Submitted QC: 2013-06-26
• Study First Posted: 2013-06-28
• Primary Completion: 2013-08
• Study Completion: 2014-12
• Status Verified: 2015-03
• Last Update Submitted: 2015-03-24
• Last Update Posted: 2015-03-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 20

Inclusion Criteria

• Age ≥18 and ≤35 yrs
• Male
• Healthy

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Exclusion Criteria

• Use of any medication
• Smoking
• History, signs or symptoms of cardiovascular disease
• History of atrial or ventricular arrhythmia
• (Family) history of myocardial infarction or stroke under the age of 65 years
• Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
• Hypertension (defined as RR systolic > 160 or RR diastolic > 90 mmHg)
• Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg)
• Renal impairment (defined as plasma creatinine >120 μmol/l)
• Liver enzyme abnormalities alkaline phosphatase>230 U/L and/or ALT>90 U/L
• Medical history of any obvious disease associated with immune deficiency
• CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxemia day
• Participation in a drug trial or donation of blood 3 months prior to the experiment
• Pre-existent lung disease or asthma
• Use of recreational drugs within 21 days prior to experiment day
• Visit to altitude >1500m within 4 weeks prior to the experiment
• Air travel with flight time over 3 hours within 4 weeks prior to the experiment
• History of acute mountain sickness
• Recent hospital admission or surgery with general anaesthesia (<3 months)
• Claustrophobia
• Feelings of discomfort during a 10 minute test wearing the transparent respiratory helmet at the screening visit

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Hypoxia	Hypoxia	Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.
Hyperoxia	Hyperoxia	Subjects will be breathing 100% of oxygen

Primary Outcome Measures

Name	Time	Method
Hypoxia Inducible Factor 1 alpha in circulating leukocytes	24 hours	Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymphocytes and monocytes as measured with flow cytometry

Secondary Outcome Measures

Name	Time	Method
Reactive Oxygen Species in circulating leukocytes	24 hours	ROS in circulating leukocytes, subclassified in neutrophils and monocytes
circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)	24 hours
cognitive function	24 hours	neuropsychologic assessment of cognitive function
Neutrophil function	24 hours
body temperature	24 hours
oxygen saturation and PaO2	24 hours
iFABP	24 hours
Brain specific proteins	24 hours
endocan	24 hours
VEGF	24 hours
cytokine production after ex vivo stimulation of leukocytes	24 hours
catecholamines	24 hours	adrenaline, noradrenaline and dopamine
adrenomedullin	24 hours
Hemodynamic parameters	24 hours	Blood pressure, heart frequency, cardiac output measurement
alkaline phosphatase	24 hours
EPO	24 hours
Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes	24 hours
Phagocytic function of circulating leukocytes	24 hours
ventilatory response	24 hours	Measures of ventilation: respiratory rate, blood gas changes
adenosine metabolism	24 hours	urine and plasma adenosine,adenosine receptor mRNA, purines
Hepcidin and iron parameters	24 hours
subjective symptoms	24 hours
high sensitive troponin	24 hours
Heart rate variability	24 hours

Trial Locations

Locations (1)

Intensive Care Medicine, Radboud University Nijmegen Medical Centre; 🇳🇱 Nijmegen, Nijmegen, Gelderland, Netherlands