Calpain mediates ischemic injury of the liver through modulation of apoptosis and necrosis

Kohli, Vivek; Madden, John F.; Bentley, Rex C.; Clavien, Pierre‐Alain

doi:10.1016/s0016-5085(99)70241-6

Cited by 155 publications

(101 citation statements)

References 61 publications

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“…Inhibition of calpain I activity reduces the injury associated with ischemia reperfusion of the brain, [65][66][67] liver, 68 and heart. 69 -72 The mechanism by which inhibitors of calpain activity protect tissues/organs against reperfusion injury is not entirely clear.…”

Section: Discussionmentioning

confidence: 99%

Calpain Inhibitor I Reduces the Development of Acute and Chronic Inflammation

Cuzzocrea

McDonald

Mazzon

et al. 2000

The American Journal of Pathology

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There is limited evidence that inhibition of the activity of the protease calpain I reduces inflammation. Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that calpain inhibitor I (given at 5, 10, or 20 mg/kg i. It is now widely accepted that the formation of pro-inflammatory cytokines [eg, tumor ecrosis factor-␣ (TNF␣), interleukin IL)Ϫ1, IL-6,or IL-8], the expression on endothelium and neutrophils of adhesion molecules (eg, VCAM-1, ICAM-1), and the overproduction of vasoactive mediators [eg, nitric oxide (NO) by inducible NO synthase (iNOS) or eicosanoids by cyclooxygenase-2 (COX-2)] play important roles in the pathophysiology of inflammation. The expression of inducible genes leading to the formation of these proteins relies on transcription factors, which are controlled by (other) inducible genes and, hence, require de novo protein synthesis or alternatively by so-called primary transcription factors. Among the latter, nuclear factor B (NF-B) has received a considerable amount of attention because of its unique mechanism of activation and its active role in cytoplasmic/nuclear signaling, and its rapid response to pathogenic stimulation of NF-B plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in inflammation. These include the genes for TNF␣, IL-1, IL-6, IL-8, VCAM-1, ICAM-1, iNOS, and COX-2, to name but a few.

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Section: Discussionmentioning

confidence: 99%

Calpain Inhibitor I Reduces the Development of Acute and Chronic Inflammation

Cuzzocrea

McDonald

Mazzon

et al. 2000

The American Journal of Pathology

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“…Several lines of evidence suggested that apoptosis critically contributes to organ viability in these models as the number of apoptotic cells correlated with duration of ischemia and animal survival, and inhibition of mediators of apoptosis such as caspases 18 or calpain-like proteases 16,19,20 ameliorated the injury. Activation of programmed cell death is possibly a ubiquitous response to ischemia and reperfusion injury as also recently documented in the heart 21 and brain.…”

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confidence: 99%

“…[34][35][36] We recently found that inhibition of calpain-like activity confers dramatic protection in the normothermic ischemic liver including prevention of apoptosis of both hepatocytes and sinusoidal endothelial cells after reperfusion. 20 Therefore, we investigated the effects of ischemic preconditioning on calpain-like activity with a specific fluorometric assay using a substrate that is not cleaved by caspase 3. 20 We also studied the effect of ischemic preconditioning on Bcl-2 expression.…”

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confidence: 99%

“…20 Therefore, we investigated the effects of ischemic preconditioning on calpain-like activity with a specific fluorometric assay using a substrate that is not cleaved by caspase 3. 20 We also studied the effect of ischemic preconditioning on Bcl-2 expression. Bcl-2 is the most ubiquitous antiapoptotic molecule 37 protecting against a variety of apoptotic stimuli.…”

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confidence: 99%

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Ischemic preconditioning protects the mouse liver by inhibition of apoptosis through a caspase-dependent pathway

et al. 1999

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A short period of ischemia and reperfusion, called ischemic preconditioning, protects various tissues against subsequent sustained ischemic insults. We previously showed that apoptosis of hepatocytes and sinusoidal endothelial cells is a critical mechanism of injury in the ischemic liver. Because caspases, calpains, and Bcl-2 have a pivotal role in the regulation of apoptosis, we hypothesized that ischemic preconditioning protects by inhibition of apoptosis through down-regulation of caspase and calpain activities and upregulation of Bcl-2. A preconditioning period of 10 minutes of ischemia followed by 15 minutes of reperfusion maximally protected livers subjected to prolonged ischemia. After reperfusion, serum aspartate transaminase (AST) levels were reduced up to 3-fold in preconditioned animals. All animals subjected to 75 minutes of ischemia died, whereas all those who received ischemic preconditioning survived. Apoptosis of hepatocytes and sinusoidal endothelial cells, assessed by in situ TUNEL assay and DNA fragmentation by gel electrophoresis, was dramatically reduced with preconditioning. Caspase activity, measured by poly (adenosine diphosphate ribose) polymerase (PARP) proteolysis and a specific caspase-3 fluorometric assay, was inhibited by ischemic preconditioning. The antiapoptotic mechanism did not involve calpain-like activity or Bcl-2 expression because levels were similar in control and preconditioned livers. In conclusion, ischemic preconditioning confers dramatic protection against prolonged ischemia via inhibition of apoptosis through down-regulation of caspase 3 activity, independent of calpain-like activity or

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“…20 Apoptosis is a central mechanism of injury in the ischemic liver. 21,22 Our group has shown that ischemic preconditioning dramatically reduces apoptosis of the sinusoidal endothelial cells and hepatocytes after reperfusion in the mouse liver. 10 We recently performed a prospective pilot study of ischemic preconditioning in 24 patients undergoing hemihepatectomies under exactly 30 minutes of inflow occlusion (Pringle maneuver).…”

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confidence: 99%