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Published on: November 10, 2011
Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase
Vincenzo La Mura1, Marcos Pasarín2, Aina Rodriguez-Vilarrupla2
1Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università di Milano, Milano, Italy.
Inducible nitric oxide synthase (iNOS) upregulation contributes to liver microvascular dysfunction during endotoxemia. Inhibiting iNOS can prevent liver injury and protect against sepsis-induced microcirculatory damage.
Area of Science:
- Physiology
- Pathology
- Pharmacology
Background:
- Sepsis-induced microvascular dysfunction contributes to organ failure.
- Intrahepatic endothelial dysfunction and systemic vascular dysfunction are observed after lipopolysaccharide (LPS) exposure.
- The role of inducible nitric oxide synthase (iNOS) in liver microcirculation during endotoxemia is not well understood.
Purpose of the Study:
- To investigate the role of iNOS induction in liver microvascular dysfunction in an isolated rat liver perfusion model during endotoxemia.
- To explore the impact of iNOS inhibition on liver microcirculation and function following LPS administration.
Main Methods:
- Male Wistar rats were administered LPS or saline, with or without the iNOS inhibitor 1400 W.
- Liver microvascular function was assessed using isolated liver perfusion.
- Molecular studies and liver function tests were performed to evaluate endothelial function, liver injury, and oxidative stress.
Main Results:
- LPS induced liver endothelial dysfunction, characterized by reduced vasodilatory response to acetylcholine and decreased eNOS phosphorylation.
- LPS administration led to liver injury, indicated by elevated transaminases and impaired indocyanin green clearance, along with increased nitrooxidative stress.
- Inhibition of iNOS ameliorated liver endothelial dysfunction, reduced liver injury, and attenuated LPS-induced nitrooxidative stress.
Conclusions:
- iNOS upregulation plays a significant role in liver microvascular dysfunction associated with endotoxemia.
- Targeting iNOS may offer a protective strategy for the liver in severe bacterial infections.
