Resveratrol protects against organ injury caused by
trauma-
hemorrhage, although the mechanism remains unknown. We have previously shown that it exerts protective effects in the liver via
estrogen receptors and their signaling. Thus, we set out to determine whether
resveratrol-mediated
estrogen receptor-dependent
p38 mitogen-activated protein kinase (MAPK)/
heme oxygenase 1 activation protects the intestine after
trauma-
hemorrhage. To study this, male Sprague-Dawley rats underwent
trauma-
hemorrhage (mean blood pressure, ~ 40 mmHg for 90 min) followed by fluid
resuscitation. Animals were pretreated with an
estrogen receptor antagonist (
ICI 182,780), a specific
p38 MAPK inhibitor (SB-203580), or a
heme oxygenase enzyme antagonist (
chromium-mesoporphyrin) 30 min before vehicle or
resveratrol (30 mg/kg) administration, followed by
resuscitation, and were killed 2 h thereafter. Intestinal water content,
myeloperoxidase activity, and TNF-α,
IL-6,
intercellular adhesion molecule 1,
cytokine-induced neutrophil
chemoattractant (CINC) 1, and CINC-3 levels and
edema of the lung were measured. Mean arterial blood pressure, cardiac output, positive maximal pressure of left ventricular increase (+dP/dtmax), and negative maximal pressure of left ventricular decrease (-dP/dtmax) were also determined. Intestinal
p38 MAPK activity and
heme oxygenase 1 expression were also determined.
Trauma-
hemorrhage led to an increase in intestinal water content,
myeloperoxidase activity, and TNF-α,
IL-6,
intercellular adhesion molecule 1, CINC-1, and CINC-3 levels. This was accompanied by a decrease in intestinal
p38 MAPK activity. Administration of
resveratrol improved all of the above parameters.
Resveratrol treatment also increased intestinal
heme oxygenase 1 expression as compared with vehicle-treated
trauma-hemorrhaged rats. Administration of
ICI 182,780, SB-203850, or
chromium-mesoporphyrin with
resveratrol abolished the
resveratrol-mediated improvement of the above parameters.
Resveratrol administration also attenuated
trauma-
hemorrhage-induced cardiac dysfunction and
edema of the lung. These results suggest that
estrogen receptor-dependent upregulation of the
p38 MAPK/
heme oxygenase 1 pathway plays a critical role in mediating the salutary effects of
resveratrol on
shock-induced intestinal injury.