Sleep and Inflammatory Resolution Pathway

Low-grade or unresolved inflammation is involved in the pathogenesis of many human diseases.
Common sleep patterns of restricting sleep during the work week and "catching up" on sleep
over the weekend lead to inflammatory upregulation that does not recover completely after the
weekend.

The goal of this proposal is to investigate, for the first time, inflammatory resolution
pathways. Inflammatory resolution mediators, such as resolvins, are derived from omega-3 free
fatty acids and actively 'turn-off' inflammation. Based on preliminary data, the
investigators hypothesize that common sleep restriction-recovery patterns disrupt
inflammatory resolution pathways, making it difficult to return to inflammatory homeostasis.
If true, pharmacologically increasing the body's natural production of endogenous
inflammatory resolution mediators may provide a way to reduce the detrimental inflammatory
consequences of common sleep restriction-recovery patterns.

The hypothesis will be tested using an experimental model that mimics common patterns of
restricting sleep on weekdays and "catching up" on sleep on the weekend. The proposal will
further utilize the unique ability of low-dose aspirin, which - like no other non-steroidal
anti-inflammatory drug - is able to activate inflammatory resolution pathways. Healthy women
and men between the ages of 18 to 65 years will be tested under three, 11-day in-hospital
stays, during which participants will be exposed to control sleep or common patterns of sleep
restriction-recovery. The three in-hospital stays will be combined with preemptive
administration of low-dose aspirin or a placebo.

Targeting inflammatory resolution pathways could provide a novel, non-behavioral strategy to
mitigate both inflammatory consequences and future disease risks in those undergoing periods
of sleep restriction-recovery patterns - a behavior pattern that is unlikely to be eradicated
in the near future, as changes in sleep are generally difficult to make and to maintain.

Inclusion Criteria:

- Women and men between the ages 18-65 years.

- Body mass index (BMI) between 18.5 and 35 kg/m2.

- For female participants: No significant discomfort during pre-menses/menses.

- Daily sleep duration between 7-9 hours, verified by electronic sleep diary data for
two weeks.

- Habitual sleep period must begin within one hour of 11:00pm (to ensure normal
entrainment).

- Negative toxicology screen, including: amphetamines, barbiturates, benzodiazepines,
cocaine, opiates, and methadone. Toxicology screening will be performed as part of the
screening lab tests; an outside lab toxicology screening will not suffice.

Exclusion Criteria:

- Active infection/disease.

- Following blood chemistry values outside of the laboratory's normal range or the range
specified below:

- WBC (range: 2.0-10.0 K/uL)

- Platelet count

- Hematocrit in range

- TSH outside of the laboratory's normal range

- Bilirubin >1.5 upper limit of normal

- ALT or AST >2.5 upper limit of normal

- Stage 4 chronic kidney disease based on CKD epi-equation

- Pre-diabetes or diabetes (HbA1c >5.7%)

- History of neurological, chronic pain, immune/inflammatory, vascular/cardiovascular
(including Raynaud syndrome), liver/kidney, metabolic disorders (including diabetes).

- Current asthma (diagnosis of asthma and either asthma symptoms present within the past
years or taking medication for asthma) and/or history of ASA induced sensitivity

- Systolic blood pressure ≥ 140mmHg and/or diastolic blood pressure ≥ 90 mmHg prior to
the initial and medical screens. Systolic blood pressure ≥ 160mmHg and/or diastolic
blood pressure ≥ 100mmHg during admissions (Stays 1, 2, and 3)

- History of gastrointestinal disorders, including esophageal reflux, gastric and
duodenal ulcers, gastrointestinal bleeding.

- Personal or family (first degree relative) history of any stroke

- History of psychiatric disorders, including major depressive disorders, bipolar
disorders, panic disorders, post-traumatic stress disorders (PTSD), thought disorders,
and substance abuse/dependence disorders.

- History of intolerance or allergy to non-steroidal anti-inflammatory drugs (NSAID).

- Sleep disorders: Sleep efficiency <80% based on polysomnographic (PSG) screening
night; respiratory disturbance index of >10 events/hour based on PSG screening night,
periodic leg movement index (PLMI) of >25/hour and/or PLMAI (PLM arousal index) of
>5/hour based on PSG screening night; restless legs syndrome, circadian rhythm
disorders, and nightmare disorders determined by diagnostic interview.

- Pregnant/nursing.

- Regular medication use other than oral contraceptives.

- Intake of non-steroidal anti-inflammatory drugs (NSAIDs) or cold/cough remedies within
the last month.

- Intake of dietary supplements containing DHA/EPA-derived fatty acids (e.g., fish oil)
within the last 3 months prior to study start.

- Donation of blood or platelets within three months prior to or in-between study arms.

- Smoking.