Abstract
IntroductionThe goal of the current study was to investigate the effect of aging on the development of endothelial dysfunction in a murine model of sepsis, and to compare it with the effect of genetic deficiency of the endothelial isoform of nitric oxide synthase (eNOS).MethodsCecal ligation and puncture (CLP) was used to induce sepsis in mice. Survival rates were monitored and plasma indices of organ function were measured. Ex vivo studies included the measurement of vascular function in thoracic aortic rings, assessment of oxidative stress/cellular injury in various organs and the measurement of mitochondrial function in isolated liver mitochondria.ResultseNOS deficiency and aging both exacerbated the mortality of sepsis. Both eNOS-deficient and aged mice exhibited a higher degree of sepsis-associated multiple organ dysfunction syndrome (MODS), infiltration of tissues with mononuclear cells and oxidative stress. A high degree of sepsis-induced vascular oxidative damage and endothelial dysfunction (evidenced by functional assays and multiple plasma markers of endothelial dysfunction) was detected in aortae isolated from both eNOS−/− and aged mice. There was a significant worsening of sepsis-induced mitochondrial dysfunction, both in eNOS-deficient mice and in aged mice. Comparison of the surviving and non-surviving groups of animals indicated that the severity of endothelial dysfunction may be a predictor of mortality of mice subjected to CLP-induced sepsis.ConclusionsBased on the studies in eNOS mice, we conclude that the lack of endothelial nitric oxide production, on its own, may be sufficient to markedly exacerbate the severity of septic shock. Aging markedly worsens the degree of endothelial dysfunction in sepsis, yielding a significant worsening of the overall outcome. Thus, endothelial dysfunction may constitute an early predictor and independent contributor to sepsis-associated MODS and mortality in aged mice.
Highlights
The goal of the current study was to investigate the effect of aging on the development of endothelial dysfunction in a murine model of sepsis, and to compare it with the effect of genetic deficiency of the endothelial isoform of nitric oxide synthase
Results endothelial isoform of nitric oxide synthase (eNOS) deficiency and aging both exacerbate the mortality of sepsis To determine whether mice exhibited an eNOS deficiencyand/or an age-associated vulnerability to sepsis, we compared mortality rates of eNOS−/− and aged (24 months) versus young mice (C57BL/6, approximately two months of age) in response to Cecal ligation and puncture (CLP)
Comparison of the surviving and non-surviving groups of animals indicates that the severity of endothelial dysfunction may be a predictor of mortality of mice subjected to CLP-induced sepsis
Summary
The goal of the current study was to investigate the effect of aging on the development of endothelial dysfunction in a murine model of sepsis, and to compare it with the effect of genetic deficiency of the endothelial isoform of nitric oxide synthase (eNOS). A life-threatening systemic inflammatory disease affects nearly 700,000 people annually in the United States. Severe sepsis occurs in one quarter of all intensive care unit (ICU) admissions and accounts for up to half of ICU bed days. Sepsis is associated with fatality rates of 20 to 40%. Sepsis-related health care costs amount to $17 billion/year in the United States alone. The frequency of sepsis is increasing by >5% per year, in excess of the growth and aging of our population. The outcome of sepsis is dramatically worse in older people: age alone is an independent predictor of mortality in sepsis [1,2]
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