Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase.

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.

[1]  H. Bruining,et al.  Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock. , 1999, Circulation.

[2]  K. Hirata,et al.  Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. , 1998, The Journal of clinical investigation.

[3]  A. Malik,et al.  In vivo expression of neutrophil inhibitory factor via gene transfer prevents lipopolysaccharide-induced lung neutrophil infiltration and injury by a beta2 integrin-dependent mechanism. , 1998, The Journal of clinical investigation.

[4]  P. Wołkow,et al.  Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats. , 1998, Circulation research.

[5]  R. McIntyre,et al.  l-Arginine prevents lung neutrophil accumulation and preserves pulmonary endothelial function after endotoxin. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[6]  D. Schwartz,et al.  Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. , 1997, The Journal of clinical investigation.

[7]  H. S. Kim,et al.  Elevated blood pressures in mice lacking endothelial nitric oxide synthase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  O. Smithies,et al.  Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Libby,et al.  Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. , 1995, The Journal of clinical investigation.

[10]  C. Nathan,et al.  Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase , 1995, Cell.

[11]  C. Thiemermann,et al.  Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Vassalli,et al.  Cloning and sequencing of mouse VCAM-1 cDNA. , 1993, Gene.

[13]  A. Malik,et al.  TNF-alpha release in endotoxemia contributes to neutrophil-dependent pulmonary edema. , 1993, The American journal of physiology.

[14]  T. Tsuda,et al.  Cytokine‐induced expression of an inducible type of nitric oxide synthase gene in cultured vascular smooth muscle cells , 1993, FEBS letters.

[15]  C. Thiemermann,et al.  Nitric oxide‐mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock , 1993, British journal of pharmacology.

[16]  C. Natanson,et al.  N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin , 1992, The Journal of experimental medicine.

[17]  Y. Kita,et al.  Sequence and expression of rat ICAM-1. , 1992, Biochimica et biophysica acta.

[18]  F. Murad,et al.  Desensitization to nitroglycerin in vascular smooth muscle from rat and human. , 1986, Biochemical pharmacology.

[19]  S. Goldblum,et al.  Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. , 1985, Journal of applied physiology.

[20]  J. Beazell,et al.  Measurement of Pulmonary Edema , 1965, Circulation research.

[21]  P. López-Jaramillo,et al.  The L-arginine: nitric oxide pathway. , 1993, Current opinion in nephrology and hypertension.