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Vol. 284, Issue 3, 1139-1146, March 1998
Department of Cell Biology and Molecular Biology (R.N.), University
of Medicine and Dentistry, School of Osteopathic Medicine, New Jersey,
Stratford, New Jersey
The role of nitric oxide (NO) and peroxynitrite in the process of
neutrophil adhesion and infiltration was investigated in a model of
hepatic ischemia-reperfusion. Male Fischer rats were subjected to 30 min of hepatic no-flow ischemia followed by 4 h of reperfusion
(I/R). I/R induced liver injury as evidenced by a 13.7-fold increase in
plasma alanine aminotransferase activity. Induction of liver injury was
associated with an increase in neutrophil accumulation in ischemic
lobes of livers [215 ± 27 polymorphonuclear neutrophil
leukocytes/50 high-power field (HPF), P < .05 compared with sham
control] and 8-fold augmentation of inducible NO synthase (NOS)
activity. However, NO levels in the liver decreased; this decrease may
be caused by peroxynitrite formation by the reaction of NO with
superoxide. Sections of ischemic lobes of the liver tissue of I/R
animals exhibited marked immunoreactivity with anti-nitrotyrosine antibody, which indicates the presence of nitrotyrosine. Administration of Nw-nitro-L-arginine methyl ester (10 mg/kg
i.v. before reperfusion) attenuated total and inducible NOS activity in
both ischemic and nonischemic lobes of liver, and reduced NO levels in
plasma and liver. However, NOS inhibition aggravated liver injury as
alanine aminotransferase increased by 61% compared with rats subjected to reperfusion injury. Neutrophil accumulation was enhanced in ischemic
(436 ± 48/50 HPF, P < .05 compared with I/R animal) and nonischemic lobes of livers (34 ± 3.2/50 HPF, P < .05 compared with sham control). NOS inhibition also attenuated
immunohistochemically detected nitrotyrosine formation, but increased
superoxide production in the liver. The NO-dependent regulation of
neutrophil accumulation in the liver may be linked closely to
P-selectin and intracellular adhesion molecule-1 expression because
inhibition of NOS resulted in significant increases in gene expression
of these two adhesion molecules (determined by reverse
transcription-polymerase chain reaction analysis). These results
suggest that NO is important in attenuating neutrophil accumulation and
liver damage in ischemia-reperfusion injury. Inhibition of NOS activity
reduces peroxynitrite formation but aggravates liver injury and
increases neutrophil accumulation, which suggests that the
anti-inflammatory function of NO is more important than the cytotoxic
potential of peroxynitrite in acute inflammation.
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