31 Apoptotic Cell Death in Sepsis

More than 210,000 people die from sepsis in the United States each year, with an annual cost of more than 16 billion dollars.1,2,3 Despite continued advances in treatment and prevention, sepsis is a growing problem, with a significant mortality rate of 28% to 50%.2,4 In the past, death from sepsis was thought be due to uncontrolled inflammation, and as a result, numerous anti-inflammatory therapeutics were developed. Uncontrolled inflammation leading to death may be true in sepsis due to certain types of pathogens (e.g., Neisseria meningitides, Clostridium perfringens)5 and in these patients anti-inflammatory therapies may help. However, large-scale clinical trials of anti-inflammatory therapies in septic patients have failed to reduce patient mortality.1 Recent research into the host’s immune response in sepsis has led to a fundamental change in the way clinicians and researchers think about this disease.6 After an initial hyper-inflammatory phase, septic patients may descend into a period of prolonged immune suppression, and it is during this period that the majority of patients die.7 Death usually occurs from multiorgan system failure brought on by the host’s inability to clear the primary infection or from a second opportunistic or nosocomial infection. One important hallmark of sepsis is widespread cell death in multiple organ systems due to both apoptosis and necrosis.6 This chapter reviews the cell types that undergo apoptosis and necrosis, the known inciting factors and mechanisms of cell death, and the impact of sepsis-induced apoptosis on morbidity and mortality, especially focusing on the importance of the lymphocyte.

Sepsis causes canonical inflammation in the immune competent host. Celsus, a Roman writer of the first century CE, was the first to enumerate the four cardinal signs of inflammation: rubor, tumor, calor, and dolor (redness, swelling, heat, and pain). A fifth clinical sign, loss of function ( functio laesa), was later added by Virchow. With the advent of cellular and molecular biology, we now have an etiologic basis of these clinical findings.

Researchers have shown in both animal models of sepsis and in septic patients that there is a complex, multiphasic inflammatory program.8 There are two competing models: one camp has proposed that sepsis is a constant mixed inflammatory state that has different local and systemic effects, whereas the other view is that sepsis has discrete hyperand hypo-inflammatory phases.6,9 The initial phase is predominantly hyper-inflammatory and is characterized by fever, hypermetabolism, muscle protein breakdown, and decreased vascular resistance.8 This phase is driven by proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which are released by cells of the innate immune system, including activated macrophages.8 As sepsis progresses, patients descend into a hypo-immune phase, which is dependent on many factors, including the virulence of the pathogen, the amount of bacterial inoculum, genetic background (polymorphisms), host comorbidities, and so forth.6 In this phase of sepsis, both the innate and adaptive immune system are compromised, evidenced by loss of delayed-type hypersensitivity response (anergy),10 a shift from a Th1 phenotype to a Th2 phenotype,11,12 increase in the proportion of T-regulatory cells,13,14 decreased major