Caspases as Drug Targets in Ischemic Organ Injury

Abstract

Caspases are intracellular cysteine proteases that mediate cell death and inflammation. Caspase-3 is a major mediator of both apoptotic and necrotic cell death. Caspase-1 mediates inflammation though the activation of the cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). Increases in both caspase-1 and -3 have been described in ischemic injury to various organs including brain, heart and kidney. Both pharmacological inhibitors and genetic approaches have been used to inhibit caspases in vivo. Pancaspase inhibitors protect against ischemic injury in brain, heart and kidney. Pancaspase inhibition also reduces cold preservation injury due to apoptosis in liver endothelial cells and prolongs animal survival after orthotopic liver transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against ischemic injury in brain, heart and kidney models of ischemia. Specifically, impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. This review focuses on studies of caspase-1 and pancaspase inhibition in ischemic injury to brain, heart and kidney. In addition, the studies of pancaspase inhibition in cold ischemic injury and organ preservation will be reviewed. The therapeutic potential of caspase inhibition in ischemic injury will be discussed.

Biomarkers Predict Progression of Acute Kidney Injury after Cardiac Surgery

“…IL-18 is specific to the renal tubules and is known to be up-regulated in response to ischemia reperfusion injury. 30 However, initial creatinine elevations after ischemic injury often do not occur until 24-48 hours after an insult (68.4% of our cohort developed AKI on or after day 2). 31 Thus, creatinine kinetics supply ample time for urinary IL-18 concentrations to dissipate, and this time lag may explain why other markers displayed more robust results.…”

Mechanisms of Renal Apoptosis in Health and Disease

“…104 -106 In vivo caspase inhibitors protect against ischemic injury in brain, heart, and kidney. 63 The pan caspase inhibitor zVAD prevents the impairment of renal function at an early time point (24 h) when administered at the time of reperfusion. 62 It is much less effective when administered 2 h later.…”

Tetramethylpyrazine protects Schwann cells from ischemia-like injury and increases cell survival in cold ischemic rat nerves

“…Ischemic injury can initiate a cascade of events that results in inflammation and cell death by apoptosis and necrosis (Faubel, Edelstein, 2005). Apoptosis is a type of cell death that occurs as a cascade of cellular machinery.…”

“…This well-established cold storage medium has also been used for preserving segments of peripheral nerves, but it was shown that peripheral nerve segments stored in UWS over a long period of time (≥3 weeks) resulted in nerves with few viable SCs that were essentially acellular conduits (Levi et al, 1994). Ischemic injury may be partly responsible for the decrease in viable SCs, because it can initiate a cascade of events that results in cell death by apoptosis and necrosis (Faubel, Edelstein, 2005).…”

“…This well-established cold storage medium has also been used for preserving segments of peripheral nerves, but it was shown that peripheral nerve segments stored in UWS over a long period of time (≥3 weeks) resulted in nerves with few viable SCs that were essentially acellular conduits (Levi et al, 1994). Ischemic injury may be partly responsible for the decrease in viable SCs, because it can initiate a cascade of events that results in cell death by apoptosis and necrosis (Faubel, Edelstein, 2005).Tetramethylpyrazine (TMP), one of the major and most important active ingredients of traditional Chinese medicine Ligusticum wallichii Franchat (Chuan Xiong), has been used to treat ischemic disorders for many years (Chun-Sheng et al, 1978;Ho, Wen, Lee, 1989). However, limited data exist on the protective effect of TMP on ischemia-like injury of SCs, and no reports have described the use of a TMP solution for nerve tissue preservation.…”