Transduction of Psychological Stress Into Systematic Inflammation by Mitochondrial DNA Signaling
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Acute Inflammatory Response to Psychological Stress
- Sponsor
- University of Pittsburgh
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- Cell-free Mitochondrial DNA
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The investigators plan to conduct a crossover experimental trial examining physiological responses to a socio-evaluative speech task under laboratory conditions. Participants will attend two laboratory sessions. At one session participants will take part in a brief laboratory stress task and at the other participants will rest for the same period. Measures of cardiovascular response will be assessed at both sessions. In addition, blood will be drawn at multiple time points across a 125 minute period to assess changes in circulating levels of cortisol, catecholamines, markers of inflammation and cell free mitochondrial DNA in response to the task. The investigators expect that the stress task will induce a specific increase in ccf-mtDNA, which will statistically mediate subsequent peak circulating Interleukin-6 and Tumor Necrosis Factor-α levels. In secondary analyses, the investigators will examine whether stress-induced increases in circulating cortisol, epinephrine, and norepinephrine levels correlate with increases in ccf-mtDNA. These studies will establish the kinetics and magnitude of psychological stress-induced ccf-mtDNA release, the association with early stress mediators, and whether ccf-mtDNA mediates the inflammatory response to acute stress in humans.
Detailed Description
The proposed study will examine physiologic responses to acute psychological challenge in the laboratory among healthy adults. It is widely accepted that there is an increase in circulating markers of inflammation following a single bout of laboratory stress. This increase in systemic inflammation is believed to contribute to the damaging health effect of psychological stress. However, to date, the biological mechanisms by which psychological stress is transduced into inflammation are unclear. The investigators' preliminary evidence suggests that mitochondrion may play a role, with stress-induced increases in circulating levels of mitochondria- derived signaling molecules that are known to modulate immune cell function and the production of pro-inflammatory cytokines. To test this possibility, the investigators plan to conduct a crossover experimental trial examining physiological responses to an evaluative speech task under laboratory conditions. The investigators have previously used this task to induce physiological arousal. The investigators plan to recruit 60 non-smoking volunteers (50% female, aged 20-50 years) and test these participants on two occasions separated by at least a month. On one occasion the participants will be exposed to the speech task. On the other occasion, the participants will rest quietly for the same period. Conditions will be counterbalanced. At both visits cardiovascular responses (heart rate, blood pressure, and heart rate variability) will be assessed as measures of autonomic activation before, during and after the task period. Participants will also have an intravenous catheter inserted and blood drawn at ten time points over the two hour testing period on each occasion. Blood samples will be sent to laboratories at the University of Pittsburgh and at Columbia University for the assessment of mitochondria-derived signalling molecules, inflammatory markers, and cortisol levels.
Investigators
Anna L. Marsland
Professor
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Generally healthy
- •Non-smokers/illicit drug users
- •Blood pressure below 140/90
- •Weight \> 110 lbs
- •BMI \< 30
- •Fluent in English
- •Women -- regular menstrual cycles over the past 12 months (defined as 21- 35 days in length)
- •Able and willing to give informed consent
- •Willing to abstain from alcohol and vigorous exercise for 24 hours, from food and drinks (other than water) for 3 hours and from non-prescription medications (other than oral contraception) for 2 days before testing.
- •Willing to attend two laboratory stress testing sessions, give blood though an intravenous catheter, undergo medical evaluation and complete psychosocial questionnaires.
Exclusion Criteria
- •Reported history of chronic systemic immune, metabolic or mitochondrial diseases, or chronic diseases that influence the central nervous, autonomic nervous or neuroendocrine systems, e.g., autoimmune disease, chronic infections, cardiovascular disease, diabetes, chronic kidney or liver disease, cancer treatment.
- •Reported psychiatric history of schizophrenia or other psychotic illness, or mood disorder.
- •Resting blood pressure \> 140/90 mmHg at baseline testing.
- •Weight \< 110 lbs
- •BMI equal to or greater than 30
- •Report currently taking glucocorticoid, anti-inflammatory, anti-retroviral, immunosuppressant, insulin, antiarrhythmic, antihypertensive, oral hypoglycemic, antidepressant, benzodiazepine or prescription weight loss medications or other medications known to influence the immune, autonomic or neuroendocrine systems.
- •For women - Post-menopausal or irregular menstrual cycles over the past 12 months. Report current pregnancy or lactation.
- •Current smokers (defined as having smoked a cigarette in the previous 3 months).
- •Current illicit drug use (defined as reported use of illicit drugs such as marijuana, cocaine or heroin in the previous 3 months).
- •Not fluent in English (have used English in everyday speaking and reading for at least 10 years)
Outcomes
Primary Outcomes
Cell-free Mitochondrial DNA
Time Frame: 5 minutes before task, and 5, 10, 20, 30, 45, 60, 75, 90 and 120 minutes after the task.
Serum levels of mitochondrial DNA assessed from blood samples
Interleukin-6
Time Frame: 5 minutes before to 5, 10, 20, 30, 45, 60, 75, 90, 120 post-task periods
Plasma levels of interleukin-6
Tumor Necrosis Factor-alpha
Time Frame: 5 minutes before to 5, 10, 20, 30, 45, 60, 75, 90, 120 post-task periods
Plasma levels of tumor necrosis factor-alpha
Secondary Outcomes
- Cortisol(5 minutes before to 10, 20, 30, 45, 60 minutes post-task periods)
- Norepinephrine(5 minutes before to 5, 10, 20, 30, & 60 minutes post-task periods)
- Depressed Mood(2 minutes before and 2-, 60- and 120-minutes post-task periods)
- Fatigue(2 minutes before and 2, 60, and 120 minutes post-task periods)
- Calm Mood(2 minutes before and 2-, 60-, and 120-minutes post-task periods)
- Heart Rate Variability(Pre-task, task, and 1-5 and 6-10 minutes post task)
- Systolic Blood Pressure(5 min pre-task and 5, 10, 20, 30, 45, 60, 75, 90, 120)
- Diastolic Blood Pressure(5 min pre-task and 5, 10, 20, 30, 45, 60, 75, 90, 120 post task onset)
- Epinephrine(5 minutes before to 5, 10, 20, 30, & 60 minutes post-task periods)
- Anger(2 minutes before and 2-, 60-, and 120-minutes post-task periods)
- Wellbeing(2 minutes before and 2-, 60- and 120-minutes post-task periods)
- Heart Rate(last 5 minutes of baseline, 5-min task-period, first two 5 minutes post-task.)
- Anxious Mood(2 minutes before and 2-, 60- and 120-minutes post-task periods)
- Vigor(2 minutes before and 2-, 60-, and 120-minutes post-task periods)