Blockade of apoptosis as a rational therapeutic strategy for the treatment of sepsis

Abstract

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.

Figure 1

Apoptotic signaling pathways as seen through death receptor ligation of TNFR or Fas (extrinsic signaling, type I cells) or through activation of the mitochondrial pathway through Bcl-2 family members (intrinsic signaling, type II cells).

Figure 2

The levels of apoptosis (Ao) seen in experimental septic mice and septic patients, as well as the mediators that affect the onset and frequency of Ao in various immune cell types.

Figure 3

A depiction of several possible mechanisms of immune suppression. (A) Illustrates the simple hypothesis (mechanism) that the immune dysfunction observed is a result of advertant/inadvertent apoptotic (Ao) loss of immune cell potential/capacity resultant from extrinsic and/or intrinsic Ao pathway activation. Here no consideration is made for Ao cell clearance. (B) Depicts a scheme in which phagocytic function is compromised, so as to block apoptotic cell clearance, subsequently allowing apoptotic cells to move into secondary necrosis, that may in turn produce by-stander tissue injury. The scenarios illustrated in C.i.-C.iii. represent the proposed effects that clearance of necrotic (C.i.) and/or apoptotic cell materials (induced by classic Ao stimuli [C.ii.] or ingestion of microbes [C.iii.])has on the developing macrophage functional phenotype (pro-inflammatory vs. anti-inflammatory/immune suppressive) is considered when phagocytic function is normal. CD36, cell differentiation antigen 36; CR, complement receptor(s); CD1d/MICA non-variant major histocompatability class 1-like antigen family; FcR, immunoglobulin constant region receptor(s); HSP, heat shock protein(s); PS, phosphotydal serine; ScavR, Scavenger receptor(s) which bind PS; TSP, thrombospondin.