Apoptosis and caspases regulate death and inflammation in sepsis

Abstract

Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic-inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.

Cell death in the host response to infection

“…During sepsis, lymphocytes are depleted by apoptosis, which leads to anergy and immunosuppression. 36 In an experimental model of sepsis, inhibition of apoptosis by selective caspase-3 inhibitors 37 or by Bcl-2 overexpression 38 was shown to lower sepsis-related mortality.…”

Neonatal monocytes express antiapoptotic pattern of Bcl-2 proteins and show diminished apoptosis upon infection with Escherichia coli

“…PICD has been shown to occur after infection with a variety of different pathogens, including Escherichia coli and group-B-Streptococci, two of the main causative agents of neonatal sepsis (9). PICD of monocytes and apoptosis of other immune cells are important for terminating inflammation (10). A former study in adult septic patients showed a poor outcome in patients with reduced monocyte apoptosis (11).…”

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

“…It has been suggested that apoptosis can contribute to the state of immunosuppression in prolonged sepsis in at least two major fashions: the programmed cell death of key effector cells, as described above, or alternatively, the capacity of apoptotic cells to induce anergy and Th2-responses in surviving immune cells such as macrophages and dendritic cells [101]. When macrophages or dendritic cells phagocytose apoptotic cells, both cell types express lower levels of co-stimulatory molecules than expected [102], while releasing large amounts of anti-inflammatory cytokines such as transforming growth factor-beta (TGF-b) Apoptosis (2009) 14:509-521 515 and IL-10 [103]; high levels of the latter cytokine a particularly poor prognostic factor in sepsis patients [104].…”

“…However, there are important theoretical and pharmacological considerations that may limit the utility of caspase-targeted approaches. First, since only a very small amount of activated caspase-3 can initiate DNA fragmentation and apoptosis, the pharmacological blockade would have have to be highly potent and penetrant [101], while caspase inhibitors at large doses can have nonspecific side effects including cytotoxicity. Anti-retroviral protease inhibitors have also been tested in murine sepsis and shown to increase survival, reduce lymphocyte apoptosis, early TNFa and late IL-6 and IL-10 levels [124].…”