The factors by which aging predisposes to critical illness are varied, complex, and not well understood. Sepsis annually kills hundreds of thousands of people in the US with associated hospital costs of billions of dollars. Of concern, sepsis incidence is increasing at more than 8% annually. Sepsis is considered a quintessential disease of old age because the incidence and mortality of severe sepsis increases exponentially as we age. Patients 65 and older account for 65% of all sepsis cases and age independently predicts sepsis mortality. Studies suggest that chronic inflammation contributes to increased morbidity and mortality in older adults. Among predisposing factors, two are underappreciated as contributing to chronic inflammation and sepsis outcomes in older adults: sleep fragmentation and blood brain barrier transport. Sleep of older adults is fragmented, and sleep disruption is associated with increased production of cytokines, including tumor necrosis factor (TNF). Aging increases the rate TNF is transported from blood-to-brain across the blood brain barrier (BBB), and TNF transported across the BBB can induce the production of more TNF within the brain. These observations suggest the intriguing hypothesis that aging, sleep fragmentation and alterations in BBB transport synergistically contribute to chronic neuroinflammation. We will test this hypothesis within the context of four Aims. We will use the well-characterized model of cecal ligation and puncture to induce sepsis in mice. We will determine the impact of aging and sleep fragmentation on sepsis outcomes (Aim 1) and quantify changes in cytokine profiles in brain and periphery (Aim 2). We will also quantify effects of aging and sleep fragmentation on the rate of TNF transport across the BBB and its accumulation in brain (Aim 3). Finally, we will inhibit cytokine actions in brain and determine effects on sepsis morbidity and mortality (Aim 4). Outcome measures for most experiments include symptoms of clinical illness (altered sleep, changes in brain temperature, reductions in water and food consumption, loss of body weight) and mortality. We have validated Luminex xMAP(R) technology for multiplex assay of cytokines from mouse brain. We will use this approach to quantify cytokine profiles in plasma and discrete brain regions (hypothalamus, hippocampus, brain stem) from the same animal. We will determine influx rates from blood-to-brain for TNF and ascertain the integrity of the BBB. Finally, we will antagonize TNF directly in brain and interfere with transcriptional regulation of TNF and other cytokines. To our knowledge, effects of aging, sleep fragmentation and alterations in BBB characteristics as determinants of sepsis outcomes have not been studied. Completion of this project will provide critical information that is currently lacking with respect to interactions among dynamic processes (aging, altered BBB parameters, sepsis) and predisposing factors (sleep fragmentation) that may contribute to negative outcomes in response to critical illness or injury.

Public Health Relevance

Sepsis is the number 1 non-cardiac killer in hospitals and is particularly lethal in adults aged 65 and over. The reason why aging is associated with increased mortality in older adults is not well understood. We hypothesize that sleep problems in older adults produce inflammation, which in turn alters the ability of the brain to respond appropriately and predisposes patients to adverse sepsis outcomes. These sleep problems before the onset of sepsis are compounded by the severe sleep disruption that occurs while patients are in the ICU.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-T (02))
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Mackiewicz, Miroslaw
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University of Washington
Schools of Medicine
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Ringgold, Kristyn M; Barf, R Paulien; George, Amrita et al. (2013) Prolonged sleep fragmentation of mice exacerbates febrile responses to lipopolysaccharide. J Neurosci Methods 219:104-12