Role of nitric oxide in recombinant tumor necrosis factor-alpha-induced circulatory shock

Zwaveling, JH; Maring, JK; Moshage, Han; vanGinkel, RJ; Hoekstra, HJ; Donse, IF; Girbes, Arj; Koops, Heimen Schraffordt

doi:10.1097/00003246-199611000-00008

Cited by 11 publications

(2 citation statements)

References 24 publications

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“…IL‐1, IL‐6, TNF‐α, IFN‐γ) are detectable during this process [4, 5, 7], it is possible that the increased expression of these mediators may be responsible for the lethal outcome of the respective infection. In fact, it has been demonstrated in several studies that TNF‐α is a potent vasodilatator [25–27]. So far, the central regulatory elements that are responsible for the increased expression of these mediators are only poorly characterized.…”

Section: Discussionmentioning

confidence: 99%

Antisense Phosphorothioate Oligonucleotides to the p65 Subunit of NF‐κB Abrogate Fulminant Septic Shock Induced by S. typhimurium in Mice

et al. 2001

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The aim of this study was to characterize the functional relevance of the transcription factor NF-kB in the pathogenesis of septic shock. BALB/c mice were infected with two wild-type (WT 1, WT 2) strains of S. typhimurium that induce NF-kB or an escape variant that lacks this ability (P21) at a dose of 1 Â 10 9 /animal, respectively. Furthermore, wild-type infected mice were treated with antisense oligonucleotides directed against NF-kB 24 h before and 3 or 6 h after infection, while mismatched oligonucleotides were used as controls. Subsequently, the clinical course, histological and immunological alterations were monitored. Infection with WT 1 and WT 2 strains led to lethal septic shock within 24±36 h. In contrast, infection with the P21 variant was not followed by fulminant septic shock. Treatment with specific antisense oligonucleotides against the p65 subunit of NF-kB 24 h before infection prevented the development of fulminant, lethal septic shock and was associated with a significant increase of survival. After 20 h, markedly depressed serum levels of interferon (IFN)-g and interleukin (IL)-6 but not IL-10 and tumour necrosis factor (TNF)-a were observed in p65 antisense-treated compared to mismatched-treated animals. These data show that the ability of S. typhimurium to induce lethal septic shock is critically dependent on their capacity to induce NF-kB.

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Section: Discussionmentioning

confidence: 99%

Antisense Phosphorothioate Oligonucleotides to the p65 Subunit of NF‐κB Abrogate Fulminant Septic Shock Induced by S. typhimurium in Mice

et al. 2001

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“…119 Moreover, in cancer patients receiving isolated limb perfusion with the anticancer agent TNF, complicated by leakage from the perfusion circuit to the general circulation, no systemic NO metabolites were found, despite substantial hypotension. 120 Therefore, other (still unknown?) vasodilating factors might be just as important as NO in causing systemic hypotension and shock.…”

Section: Septic Shock: Other Vasorelaxing Therapeutic Targets?mentioning

confidence: 99%

Nitric oxide in shock

Cauwels

2007

Kidney International

136

118

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Refractory hypotension with end-organ hypoperfusion and failure is an ominous feature of shock. Distributive shock is caused by severe infections (septic shock) or severe systemic allergic reactions (anaphylactic shock). In 1986, it was concluded that nitric oxide (NO) is the endothelium-derived relaxing factor that had been discovered 6 years earlier. Since then, NO has been shown to be important for the physiological and pathological control of vascular tone. Nevertheless, although inhibition of NO synthesis restores blood pressure, NO synthase (NOS) inhibition cannot improve outcome, on the contrary. This implies that NO acts as a double-edged sword during septic shock. Consequently, the focus has shifted towards selective inducible NOS (iNOS) inhibitors. The contribution of NO to anaphylactic shock seems to be more straightforward, as NOS inhibition abrogates shock in conscious mice. Surprisingly, however, this shock-inducing NO is not produced by the inducible iNOS, but by the so-called constitutive enzyme endothelial NOS. This review summarizes the contribution of NO to septic and anaphylactic shock. Although NOS inhibition may be promising for the treatment of anaphylactic shock, the failure of a phase III trial indicates that other approaches are required for the successful treatment of septic shock. Amongst these, high hopes are set for selective iNOS inhibitors. But it might also be necessary to shift gears and focus on downstream cardiovascular targets of NO or on other vasodilating phenomena.

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