Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis.
OBJECTIVE
Nitrosative stress resulting from increased nitric oxide (NO) synthesis contributes to the pathogenesis of chronic inflammatory diseases, including chronic viral hepatitis. Our goal was to assess the expression of inducible nitric oxide synthase (iNOS) and the formation of nitrotyrosine (NTY), as a marker of nitrosative stress, in liver biopsies from primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) patients.


METHODS
Intrahepatic expression of iNOS and NTY was measured immunohistochemically and compared to histological scores of the severity of liver disease.


RESULTS
Hepatocellular iNOS expression was observed in liver sections from PBC patients (with a diffuse lobular distribution) and from AIH patients (marked staining in areas of pronounced inflammation and necrosis), but not in control liver sections, including non-autoimmune cholestatic liver disease. Liver samples from PBC and AIH patients, but not from controls, showed NTY accumulation in clusters of hepatocytes and Kupffer cells. Increased iNOS expression and NTY accumulation correlated with the histological severity of PBC or AIH, especially with the degree of inflammation.


CONCLUSIONS
Patients with PBC and AIH showed an enhanced intrahepatic iNOS expression and NTY accumulation, related to the histological severity of liver disease, consistent with NO-mediated nitration of hepatocellular proteins contributing to liver damage in both diseases.
Sanz-Cameno
Paloma
P
Liver Unit, Hospital de la Princesa, Autonomous University of Madrid, Diego de León 62, E-28006 Madrid, Spain.
Medina
Jesús
J
García-Buey
Luisa
L
García-Sánchez
Asunción
A
Borque
María J
MJ
Martín-Vílchez
Samuel
S
Gamallo
Carlos
C
Jones
E Anthony
EA
Moreno-Otero
Ricardo
R
D000328:Adult; D002908:Chronic Disease; D005260:Female; D019693:Hepatitis, Autoimmune / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012720:Severity of Illness Index; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism*
C002744:3-nitrotyrosine; D014443:Tyrosine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II