Blockade of apoptosis as a rational therapeutic strategy for the treatment of sepsis.
Over time it has become clear that, much like other organ systems, the function and responsiveness of the immune system is impaired during the course of sepsis and that this is a precipitous event in the decline of the critically ill patient/animal. One hypothesis put forward to explain the development of septic immune dysfunction is that it is a pathological result of increased immune cell apoptosis. Alternatively, it has been proposed that the clearance of increased numbers of apoptotic cells may actively drive immune suppression through the cells that handle them. Here we review the data from studies involving septic animals and patients, which indicate that loss of immune cells, as well as non-immune cells, in some cases, is a result of dysregulated apoptosis. Subsequently, we will consider the cell death pathways, i.e. 'extrinsic' and/or 'intrinsic', which are activated and what cell populations may orchestrate this dysfunctional apoptotic process, immune and/or non-immune. Finally, we will discuss potentially novel therapeutic targets, such as caspases, death receptor family members (e.g. tumour necrosis factor, Fas) and pro-/anti apoptotic Bcl-family members, and approaches such as caspase inhibitors, the use of fusion proteins, peptidomimetics and siRNA, which might be considered for the treatment of the septic patient.
Ayala
Alfred
A
Shock-Trauma Research Laboratory, Division of Surgical Research, Department of Surgery, Rhode Island Hospital / Brown University School of Medicine, Providence, RI 02903, USA.
Wesche-Soldato
Doreen E
DE
Perl
Mario
M
Lomas-Neira
Joanne L
JL
Swan
Ryan
R
Chung
Chun-Shiang
CS
D000818:Animals; D017209:Apoptosis; D006801:Humans; D018805:Sepsis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology