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

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.

Study Overview

• Status: Completed
• Conditions: Hypoxia; Hyperoxia
• Intervention / Treatment: Other: Hypoxia; Other: Hyperoxia

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Gelderland
    • Nijmegen, Nijmegen, Gelderland, Netherlands, 6500 HB
      • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Hypoxia; Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.	Other: Hypoxia; Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.
EXPERIMENTAL: Hyperoxia; Subjects will be breathing 100% of oxygen	Other: Hyperoxia; Subjects will be breathing 100% oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypoxia Inducible Factor 1 alpha in circulating leukocytes	Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymphocytes and monocytes as measured with flow cytometry	24 hours

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Dorien Kiers, MD, Intensive Care Medicine, Radboud University Nijmegen Medical Centre; Study Director: Peter Pickkers, MD,PhD, Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 26, 2013
• First Submitted That Met QC Criteria: June 26, 2013
• First Posted (ESTIMATE): June 28, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): March 25, 2015
• Last Update Submitted That Met QC Criteria: March 24, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Inflammation; Hypoxia; Oxygen; Hyperoxia; Innate immunity
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hypoxia; Hyperoxia
• Other Study ID Numbers: OX1