title: Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase.
abstract: BACKGROUND
  Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice.
  
  
  RESULTS
  LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97+/-3 to 59+/-3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84+/-4 to 71+/-4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice.
  
  
  CONCLUSIONS
  Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
authors.affiliation: First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: S
authors.initials: S
authors.lastname: Kawashima
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
authors.forename: M
authors.initials: M
authors.lastname: Ozaki
authors.forename: T
authors.initials: T
authors.lastname: Ueyama
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.forename: N
authors.initials: N
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Hirata
authors.forename: H
authors.initials: H
authors.lastname: Akita
authors.forename: M
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D001011:Aorta / Q000737:chemistry; D001794:Blood Pressure; D006152:Cyclic GMP / Q000032:analysis; D004487:Edema / Q000209:etiology; D005260:Female; D006098:Granulocytes / Q000201:enzymology / Q000502:physiology; D007022:Hypotension / Q000209:etiology / Q000517:prevention & control; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D009566:Nitrates / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood*; D009929:Organ Size; D009195:Peroxidase / Q000032:analysis; D012772:Shock, Septic / Q000097:blood* / Q000235:genetics / Q000473:pathology; D014664:Vasodilation
chemical_list: D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP