Abstract
Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i.p. After 48 hours, animals were sacrificed to collect blood, spleen and kidney. The human component of our study utilized blood samples obtained from patients in the Trauma Department and samples collected 7 days later in those patients who developed sepsis. Telomere length was measured by quantitative PCR. Since oxidative stress is a known inducer of telomere shortening, thiobarbituric acid reactive substances and superoxide dismutase (SOD) activity were analyzed in order to evaluate oxidative stress burden. Induction of endotoxemia in mice resulted in significant telomere shortening in spleen and kidney. Blood cells from patients that progressed to sepsis also exhibited a statistically significant reduction of telomere length. Endotoxemia in mice also induced an early-onset increase in oxidative stress markers, but was not associated with a downregulation of telomerase protein expression. We conclude that endotoxemia and sepsis induce telomere shortening in various tissues and hypothesize that this may contribute to the pathogenesis of the delayed pathophysiological events in sepsis survivors.
Highlights
Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection [1]
Because from a clinician’s point of view the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging, in this study we evaluated whether sepsis can lead to telomere shortening
Murine Endotoxemia Induces Telomere Shortening in Various Tissues
Summary
Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection [1]. mediators as well as reactive oxygen species; these species are known to mediate and amplify some of the pathophysiologic events during the exacerbated inflammatory response. The ends of chromosomes are protected from degradation by repetitive sequences of TTAGGG and associated proteins. This region, called telomere, plays an important role in chromosome-chromosome fusions, DNA damage recognition, chromosome replication and nuclear organization [11]. The telomeric sequence ensures the annealing of telomerase, an enzyme responsible for complete telomere replication, minimizing progressive telomere shortening during cellular division [13]. The telomere region is susceptible to damage caused by oxidative stress, among other epigenetic events [16]. Telomere shortening is a hallmark and putative causative event in physiological aging [12,14]
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