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B and organ injury/dysfunction in hemorrhagic shock
* Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, London EC1M 6BQ, U.K.;
Department of Physiology and Pharmacology, University of Strathclyde, SIBS, Glasgow, G40NR, Scotland; and
Institute of Pharmacology, School of Medicine, University of Messina, Messina 98123, Italy
1Correspondence: Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K. E-mail: c.thiemermann{at}mds.qmw.ac.uk
There is limited evidence that inhibition of the activity of the
cytosolic cysteine protease calpain reduces ischemia/reperfusion
injury. The multiple organ injury associated with hemorrhagic shock is
due at least in part to ischemia (during hemorrhage) and reperfusion
(during resuscitation) of target organs. Here we investigate the
effects of calpain inhibitor I on the organ injury (kidney, liver,
pancreas, lung, intestine) and dysfunction (kidney) associated with
hemorrhagic shock in the anesthetized rat. Hemorrhage and resuscitation
with shed blood resulted in an increase in calpain activity (heart),
activation of NF-
B (kidney), expression of iNOS and COX-2 (kidney),
and the development of multiple organ injury and dysfunction, all of
which were attenuated by calpain inhibitor I (10 mg/kg i.p.),
administered 30 min prior to hemorrhage. Chymostatin, a serine protease
inhibitor that does not prevent the activation of NF-B, had no
effect on the organ injury/failure caused by hemorrhagic shock.
Pretreatment (for 1 h) of murine macrophages or rat aortic smooth
muscle cells (activated with endotoxin) with calpain inhibitor I
attenuated the binding of activated NF-B to DNA and the degradation
of IB
, IBß, and IB
. Selective inhibition of iNOS
activity with L-NIL reduced the circulatory failure and liver injury,
while selective inhibition of COX-2 activity with SC58635 reduced the
renal dysfunction and liver injury caused by hemorrhagic shock. Thus,
we provide evidence that the mechanisms by which calpain inhibitor I
reduces the circulatory failure as well as the organ injury and
dysfunction in hemorrhagic shock include 1) inhibition
of calpain activity, 2) inhibition of the activation of
NF-B and thus prevention of the expression of NFB-dependent
genes, 3) prevention of the expression of iNOS, and
4) prevention of the expression of COX-2. Inhibition of
calpain activity may represent a novel therapeutic approach for the
therapy of hemorrhagic shock.—McDonald, M. C., Mota-Filipe, H.,
Paul, A., Cuzzocrea, S., Abdelrahman, M., Harwood, S., Plevin, R.,
Chatterjee, P. K., Yaqoob, M. M., Thiemermann, C. Calpain
inhibitor I reduces the activation of nuclear factor-B and organ
injury/dysfunction in hemorrhagic shock.
Key Words: calpain • cyclo-oxygenase • endotoxin • hemorrhage • multiple organ failure • nitric oxide • reperfusion injury
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