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.
Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase / V. La Mura, M. Pasarín, A. Rodriguez-Vilarrupla, J.C. García-Pagán, J. Bosch, J.G. Abraldes. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 61:6(2014 Dec 01), pp. 1321-1327.
|Titolo:||Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase|
LA MURA, VINCENZO (Primo)
|Parole Chiave:||1400W; Multi organ failure; Oxidative stress; Sinusoidal endothelial cells|
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
Settore MED/12 - Gastroenterologia
Settore MED/17 - Malattie Infettive
|Data di pubblicazione:||1-dic-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jhep.2014.07.014|
|Appare nelle tipologie:||01 - Articolo su periodico|