Liver sinusoidal endothelial dysfunction after LPS administration

A role for inducible-nitric oxide synthase

Vincenzo La Mura, Marcos Pasarín, Aina Rodriguez-Vilarrupla, Juan Carlos García-Pagán, Jaime Bosch, Juan G. Abraldes

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background & Aims Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. Methods All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. Results At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser1176. This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. Conclusions iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection.

Original languageEnglish
Pages (from-to)1321-1327
Number of pages7
JournalJournal of Hepatology
Volume61
Issue number6
DOIs
Publication statusPublished - Dec 1 2014

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Nitric Oxide Synthase Type II
Lipopolysaccharides
Liver
Liver Diseases
Endotoxemia
Up-Regulation
Perfusion
Liver Function Tests
Wounds and Injuries
Microcirculation
Transaminases
Bacterial Infections
Acetylcholine
Blood Vessels
Wistar Rats
Sepsis
Phosphorylation
Injections

Keywords

  • 1400W
  • Multi organ failure
  • Oxidative stress
  • Sinusoidal endothelial cells

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

La Mura, V., Pasarín, M., Rodriguez-Vilarrupla, A., García-Pagán, J. C., Bosch, J., & Abraldes, J. G. (2014). Liver sinusoidal endothelial dysfunction after LPS administration: A role for inducible-nitric oxide synthase. Journal of Hepatology, 61(6), 1321-1327. https://doi.org/10.1016/j.jhep.2014.07.014

Liver sinusoidal endothelial dysfunction after LPS administration : A role for inducible-nitric oxide synthase. / La Mura, Vincenzo; Pasarín, Marcos; Rodriguez-Vilarrupla, Aina; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G.

In: Journal of Hepatology, Vol. 61, No. 6, 01.12.2014, p. 1321-1327.

Research output: Contribution to journalArticle

La Mura, V, Pasarín, M, Rodriguez-Vilarrupla, A, García-Pagán, JC, Bosch, J & Abraldes, JG 2014, 'Liver sinusoidal endothelial dysfunction after LPS administration: A role for inducible-nitric oxide synthase', Journal of Hepatology, vol. 61, no. 6, pp. 1321-1327. https://doi.org/10.1016/j.jhep.2014.07.014
La Mura, Vincenzo ; Pasarín, Marcos ; Rodriguez-Vilarrupla, Aina ; García-Pagán, Juan Carlos ; Bosch, Jaime ; Abraldes, Juan G. / Liver sinusoidal endothelial dysfunction after LPS administration : A role for inducible-nitric oxide synthase. In: Journal of Hepatology. 2014 ; Vol. 61, No. 6. pp. 1321-1327.
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AB - Background & Aims Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. Methods All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. Results At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser1176. This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. Conclusions iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection.

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