title: Endothelial dysfunction is a potential contributor to multiple organ failure and mortality in aged mice subjected to septic shock: preclinical studies in a murine model of cecal ligation and puncture.
abstract: BACKGROUND
  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).
  
  
  METHODS
  Cecal 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.
  
  
  RESULTS
  eNOS 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.
  
  
  CONCLUSIONS
  Based 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.
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.forename: Gábor
authors.initials: G
authors.lastname: Oláh
authors.forename: Attila
authors.initials: A
authors.lastname: Brunyánszki
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Herzig
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Ungvári
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002432:Cecum; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009026:Mortality / Q000639:trends; D009102:Multiple Organ Failure / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D011677:Punctures / Q000009:adverse effects; D012772:Shock, Septic / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*