Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock

M.C. McDonald, H. Mota-Filipe, A. Paul, S. Cuzzocrea, M. Abdelrahman, S. Harwood, R.J. Plevin, P.K. Chatterjee, M.M. Yaqoob, C. Thiemermann

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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-kappaB (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-kappaB, 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-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon. 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-kappaB and thus prevention of the expression of NFkappaB-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.
LanguageEnglish
Pages171-186
Number of pages15
JournalFASEB Journal
Volume15
Issue number1
Publication statusPublished - 2001

Fingerprint

Calpain
Hemorrhagic Shock
NF-kappa B
Chemical activation
Liver
Resuscitation
Kidney
Wounds and Injuries
Rats
Multiple Trauma
Hemorrhage
Serine Proteinase Inhibitors
Cysteine Proteases
Macrophages
Shock
Endotoxins
Muscle
Blood
Genes
Cells

Keywords

  • calpain inhibitor
  • organ injury
  • calpain
  • hemorrhagic shock
  • circulatory failure
  • resuscitation
  • biomedical science

Cite this

McDonald, M. C., Mota-Filipe, H., Paul, A., Cuzzocrea, S., Abdelrahman, M., Harwood, S., ... Thiemermann, C. (2001). Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. FASEB Journal, 15(1), 171-186.
McDonald, M.C. ; Mota-Filipe, H. ; Paul, A. ; Cuzzocrea, S. ; Abdelrahman, M. ; Harwood, S. ; Plevin, R.J. ; Chatterjee, P.K. ; Yaqoob, M.M. ; Thiemermann, C. / Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. In: FASEB Journal. 2001 ; Vol. 15, No. 1. pp. 171-186.
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McDonald, MC, Mota-Filipe, H, Paul, A, Cuzzocrea, S, Abdelrahman, M, Harwood, S, Plevin, RJ, Chatterjee, PK, Yaqoob, MM & Thiemermann, C 2001, 'Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock' FASEB Journal, vol. 15, no. 1, pp. 171-186.

Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. / McDonald, M.C.; Mota-Filipe, H.; Paul, A.; Cuzzocrea, S.; Abdelrahman, M.; Harwood, S.; Plevin, R.J.; Chatterjee, P.K.; Yaqoob, M.M.; Thiemermann, C.

In: FASEB Journal, Vol. 15, No. 1, 2001, p. 171-186.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock

AU - McDonald, M.C.

AU - Mota-Filipe, H.

AU - Paul, A.

AU - Cuzzocrea, S.

AU - Abdelrahman, M.

AU - Harwood, S.

AU - Plevin, R.J.

AU - Chatterjee, P.K.

AU - Yaqoob, M.M.

AU - Thiemermann, C.

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AB - 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-kappaB (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-kappaB, 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-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon. 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-kappaB and thus prevention of the expression of NFkappaB-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.

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McDonald MC, Mota-Filipe H, Paul A, Cuzzocrea S, Abdelrahman M, Harwood S et al. Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. FASEB Journal. 2001;15(1):171-186.