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(Circulation. 2000;101:931.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Resistance to Endotoxin Shock in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase

Tomoya Yamashita, MD; Seinosuke Kawashima, MD, PhD; Yoshitaka Ohashi, MD, PhD; Masaori Ozaki, MD; Tomomi Ueyama, MD, PhD; Tatsuro Ishida, MD, PhD; Nobutaka Inoue, MD, PhD; Ken-ichi Hirata, MD, PhD; Hozuka Akita, MD, PhD; Mitsuhiro Yokoyama, MD, PhD

From the First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.

Correspondence to Seinosuke Kawashima, MD, PhD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp

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.

Methods and 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.

Key Words: nitric oxide • cell adhesion molecules • lung • shock

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