Reperfusion Injury After Hemorrhage: A Collective Review

G D. Rushing, MD; L D. Britt, MD, MPH

Disclosures

Annals of Surgery. 2008;247(6):929-937. 

In This Article

Apoptosis and Reperfusion Injury

Programmed cell death, or apoptosis, is a natural and integral part of cellular growth and development. Apoptosis is also a known protective reaction to multiple types of cellular damage such as infection, inflammation, or cancer. NF-κB is known to protect against apoptosis via transcription of specific inhibitory proteins.[95,96] There is some evidence that NF-κB is an integral part of apoptosis via cross talk with known apoptotic genes of the mitogen activated protein kinase (MAPK) family: c-Jun Kinase (JNK) and p38-MAPK.[97] There are 3 known isoforms of JNK: JNK1, JNK2, and JNK3.[98] Although p-38 MAPK is activated during ischemia, and stays activated during reperfusion, JNK proteins are activated only with reperfusion. JNKs can be activated by TNF-α via a secondary messenger system, which also activates NF-κB (Figure 3). Tissue culture studies suggest that JNK is involved in fibroblast and neural cells apoptosis.[99,100,101,102,103] However, gene knockout studies utilizing mice demonstrate that JNK may be involved in protection against apoptosis, confusing the issue.[102,103] The mechanism by which JNK is involved in apoptosis remains unknown. Further research is underway to determine whether JNK initiates apoptosis or simply modulates it.

Apoptosis in reperfusion injury. The secondary messenger TRAF-2 associated with both the inflammatory cascade and apoptosis, activates the proapoptotic protein c-Jun Kinase via MAPKKK. This in turn causes intrinsic apoptosis via the mitochondria activating caspases 8 and 10. These in turn are sent to the nucleus to fragment DNA for programmed cell death.

Mitochondria, already involved in reperfusion injury as discussed above, are central to apoptotic pathways as well. Members of the B cell lymphoma-2 family activate the mitochondrial apoptotic pathway after cleavage by JNK (Figure 3). The mitochondrial permeability transition pore is activated by interaction with proapoptotic factors such as BAX, BAD, and eNOS.[104,105,106] Activation of this protein allows for egress of cytochrome c and other proapoptotic proteins.[105] Apoptotic factors, released from the mitochondria, cause activation of the enzymes caspase 3 and caspase 9.[107,108] These caspases are instrumental in DNA fragmentation and subsequent cell death. Caspase inactivation is another method in which NF-κB protects against apoptosis.[99,103] Specifically, NF-κB activation through the phosphatidylinositol 3 kinase-AKT pathway leads to phosphorylation and inactivation of caspases 3 and 9.

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