Clinical assessment of blood leukocytes, serum cytokines, and serum immunoglobulins as responses to sleep deprivation in laboratory rats

Abstract

The specific systems and mechanisms affected by sleep deprivation that may perpetuate disease processes in humans still are speculative. In laboratory rats, prolonged sleep deprivation induces a state marked by abnormal control over indigenous bacteria that results in transient infections of internal tissues and eventual lethal septicemia. The present studies investigated changes in blood, serum, and bone marrow parameters that may provide diagnostic clues to immunopathology. Prolonged sleep deprivation was produced in rats by the disk-over-water method, a well-established and selective means that does not interfere with normal waking behaviors. Measurements included bone and blood differential white blood cell counts, multiple serum cytokines and chemokines, several major Ig classes and subclasses, and serum endotoxin concentrations. The results indicated mild, regenerative neutrophilia in sleep-deprived rats, initially accompanied by immature neutrophils and later by monocytosis. The corresponding serum cytokine profile revealed an evolving proinflammatory state, particularly by high incidence of interleukin-1beta, implicating mononuclear phagocytes and resident tissue cells as main intermediary sources. In addition, multiple serum Ig classes were increased by sleep deprivation without experimental administration of an exogenous antigen. Despite this immune activation, there was failure to eradicate invading bacteria and toxins, suggesting competing anti-inflammatory processes or interference with immune effector functions during sleep deprivation. Nearly all of the immune-related events that emerged as responses to sleep deprivation have been implicated as etiological or provocative factors in other disease processes and may provide means by which sleep deprivation as a risk factor in disease may become understood.

Repeated sleep restriction in rats leads to homeostatic and allostatic responses during recovery sleep

“…We have recently used the RSR paradigm to demonstrate that rats allowed to sleep for only 4 h per day for 8 consecutive days have increased basal corticosterone levels and develop pronounced changes in the reactivity of the hypothalamo-pituitary-adrenal axis to stress (18). RSR and other forms of SD have also been shown to alter regulation of corticosterone (18)(19)(20) and proinflammatory cytokine levels (21,22), elevate markers of oxidative stress (23), and promote neurodegenerative processes in the hippocampus (24,25).…”

“…Indeed, RSR is associated with elevations in corticosterone (18)(19)(20), sympathetic tone, and cytokine levels (13,21,22), important mediators of allostasis and allostatic load. We have used the current RSR model (4-h sleep per day for 5 consecutive days) to demonstrate elevated corticosterone levels on SD1 and SD5, even when blood samples were collected after the 4-h sleep opportunity (unpublished data).…”

Recurrent restriction of sleep and inadequate recuperation induce both adaptive changes and pathological outcomes

“…However, rats that obtain nearly half-normal sleep amounts during the same time period do not develop severe pathology and do not die (20,53,55,62). They typically do, however, show abnormalities in metabolic, hormonal, and immune-related parameters that are less severe than those observed under total sleep deprivation conditions (2,18,20,21,24,28). Whether these changes are clinically important and whether an individual can adapt to sub-par sleep amounts are issues that bear on the relevance of sleep to physical health and its role in development and recuperation from disease.…”

“…83). Already well established is the fact that acutely sustained total sleep deprivation in laboratory rats results in a progressive negative energy balance (2, 20, 28), suppression of major anabolic hormones (21, 24), and immune-related abnormalities (18,19,26,27) that turn lethal after an average of 16 to 21 days (20,53,55,62). However, rats that obtain nearly half-normal sleep amounts during the same time period do not develop severe pathology and do not die (20,53,55,62).…”

“…Each sleep-restriction period lasted 10 days, which is known to be tolerated in rats under acute sleep-loss conditions (2,18,20,21,24,28,53,55). Each intervening period of sleep ad libitum lasted 2 days, which previously has been shown to normalize energy expenditure and antioxidant parameters in totally sleepdeprived rats (22,23).…”