Hemorrhagic shock and
resuscitation induces
pulmonary inflammation that leads to
acute lung injury.
Biliverdin, a metabolite of
heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and
anti-oxidant effects. This study aimed to examine the effects of intravenous
biliverdin administration on
lung injury induced by
hemorrhagic shock and
resuscitation in rats.
Biliverdin or vehicle was administered to the rats 1 h before
sham or
hemorrhagic shock-inducing surgery. The
sham-operated rats underwent all
surgical procedures except
bleeding. To induce
hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by
resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2'
deoxyguanosine levels in the lungs.
Hemorrhagic shock and
resuscitation resulted in prominent histopathological damage, including congestion,
edema, cellular infiltration, and
hemorrhage.
Biliverdin administration prior to
hemorrhagic shock and
resuscitation significantly ameliorated these
lung injuries as judged by histopathological improvement. After
hemorrhagic shock and
resuscitation, inflammatory gene expression of
tumor necrosis factor-α and
inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when
biliverdin was administered prior to
hemorrhagic shock and
resuscitation. Moreover, after
hemorrhagic shock and
resuscitation, lung 8-hydroxy-2'
deoxyguanosine levels in
mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold.
Biliverdin administration prior to
hemorrhagic shock and
resuscitation decreased mitochondrial 8-hydroxy-2'
deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that
biliverdin administration after
hemorrhagic shock and
resuscitation had protective effects on
lung injury. Our findings suggest that
biliverdin has a protective role, at least in part, against
hemorrhagic shock and
resuscitation-induced
lung injury through anti-inflammatory and
anti-oxidant mechanisms.