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. 2014 Dec 1;37(12):1929-40.
doi: 10.5665/sleep.4244.

Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats

Carol A Everson  1 , Christopher J Henchen  1 , Aniko Szabo  2 , Neil Hogg  3
Affiliations

Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats

Carol A Everson et al. Sleep. .

Abstract

Study objectives: Increased cell injury would provide the type of change in constitution that would underlie sleep disruption as a risk factor for multiple diseases. The current study was undertaken to investigate cell injury and altered cell fate as consequences of sleep deprivation, which were predicted from systemic clues.

Design: Partial (35% sleep reduction) and total sleep deprivation were produced in rats for 10 days, which was tolerated and without overtly deteriorated health. Recovery rats were similarly sleep deprived for 10 days, then allowed undisturbed sleep for 2 days. The plasma, liver, lung, intestine, heart, and spleen were analyzed and compared to control values for damage to DNA, proteins, and lipids; apoptotic cell signaling and death; cell proliferation; and concentrations of glutathione peroxidase and catalase.

Measurements and results: Oxidative DNA damage in totally sleep deprived rats was 139% of control values, with organ-specific effects in the liver (247%), lung (166%), and small intestine (145%). Overall and organ-specific DNA damage was also increased in partially sleep deprived rats. In the intestinal epithelium, total sleep deprivation resulted in 5.3-fold increases in dying cells and 1.5-fold increases in proliferating cells, compared with control. Recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage.

Conclusions: These findings provide physical evidence that sleep loss causes cell damage, and in a manner expected to predispose to replication errors and metabolic abnormalities; thereby providing linkage between sleep loss and disease risk observed in epidemiological findings. Properties of recovery sleep include biochemical and molecular events that restore balance and decrease cell injury.

Keywords: 8-hydroxydeoxyguanosine; apoptosis; cell injury; lipid peroxidation; oxidative stress.

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Figures

Figure 1
Figure 1
8-hydroxydeoxyguanosine (8-OHdG) concentrations indicative of DNA damage in ambulation controls (ACs; gray bar, n = 11) and in partially (hatched bar) and totally (solid bar) sleep deprived rats during 10 days of sleep loss (n = 8–11 per group), and after 2 days of recovery sleep after sleep loss (n = 6–7 per group). Values are shown for the liver (A), jejunum (B), lung (C), and heart (D) concentrations of 8-OHdG in pg/μg DNA, normalized to intra-assay controls (Ctrl) and expressed as the geometric means ± standard error. ** P < 0.01, *** P < 0.001, and **** P < 0.0001 for the comparison between deprivation and AC conditions. † P < 0.05 and ‡ P < 0.01 for the comparison between recovery and deprivation conditions.
Figure 2
Figure 2
Mean concentrations of isoprostane (lipid damage) by experimental conditions in ambulation control (AC; gray bar, n = 6) and in partially (hatched bar) and totally (solid bar) sleep deprived rats during 10 days of sleep loss (n = 4–7 per group), and after 2 days of recovery sleep after sleep loss (n = 6 per group). Values are shown for plasma and liver, expressed as the geometric means ± standard error. * P
Figure 3
Figure 3
The number of dead cells in the jejunum. Left: representative micrographs (40X magnification) illustrate the distribution of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells localized mainly in the apical third of a villus in an ambulation control (A) and a sleep deprived (B) rat. Right: results of quantitative analysis in ambulation control (AC) rats (n = 7) and in partially and totally sleep deprived rats during 10 days of sleep loss (n = 7–11 per group), and after 2 days of recovery sleep after sleep loss (n = 5–6 per group). The bars are the total number of dead cells in the apical third of the villi in the jejunum, further subcategorized as among the columnar epithelium or in the lamina propria. For comparison of differences from AC, * P < 0.05 for a difference in dead cell numbers in the epithelium of total sleep loss condition and † P < 0.05 for a difference in dead cell number in the lamina propria of partially sleep deprived rats. For comparison with the respective sleep deprivation condition, **** P < 0.0001 for a difference in dead cell number in the epithelium and § P < 0.05 and ‡ P < 0.01 for a difference in dead cell numbers in the lamina propria.
Figure 4
Figure 4
Replication of cells affected by sleep loss. Left: representative micrographs (100X magnification) illustrate bromodeoxyuridine (BrdU) incorporation into proliferating cells in the crypts of jejunum in an ambulation control (A) and a sleep deprived rat (B). Right: results of quantitative analysis results in ambulation control (AC) rats (gray bar, n = 7) and in partially (hatched bar) and totally (solid bar) sleep deprived rats during 10 days of sleep loss (n = 7–9 per group), and after 2 days of recovery sleep after sleep loss (n = 6–7 per group). Values shown are the number of positively labeled cells relative to the total number of crypt cells, expressed as the mean ± standard error. * P < 0.05 for the comparison of differences between sleep deprivation and AC and ** P < 0.01 for the comparison between recovery and sleep deprivation.
Figure 5
Figure 5
Dead cells in the lung in ambulation control (AC) rats (gray bar, n = 8) and in partially (hatched bar) and totally (solid bar) sleep deprived rats during 10 days of sleep loss (n = 8–11 per group), and after 2 days of recovery sleep after sleep loss (n = 6–7 per group). Values are expressed as the geometric mean ± standard error of positive cells relative to the area measured. * P
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