Not with a Bang But a Whimper: Apoptosis in the Pathogenesis of Systemic Inflammation

Abstract

Life, by its very de~nition, is the controlled growth and differentiation of embryonic stem cells. The fusion of sperm and ovum creates a unicellular entity that has the potential, through cell division and differentiation, to become an almost incomprehensibly complex collection of in excess of one trillion cells, interacting harmoniously as a unique individual. The precision and predictability of the process, occurring within a limited time span of days to years, is a source of in~nite curiosity and wonder for the biological scientist. The richness and passion that accompanies this process of biologic multiplication, provides the poet with an eternal source of inspiration. But it has only recently been appreciated that the controlled elimination of cells is as important to normal development as their initial growth. Development in utero is accompanied by biologic sculpting that, for example, transforms a _ipper into a hand with delicate ~ngers. Embryologic structures, necessary intermediates in the process of organ development, must be eliminated in the mature individual. And throughout life, controlled cell death plays a critical role in the turnover and renewal of epithelial surfaces, in the elimination of damaged or transformed cells, and in the involution of the massive cellular proliferation that accompanies in_ammation and tissue repair. This biologic process resulting in the tightly regulated death of living cells, has been termed apoptosis. First recognized more than a century ago, apoptosis has only recently captured scienti~c interest as a fundamental process with critical implications for disciplines as diverse as embryology, neurology, oncology, and infectious diseases. The basic template for the expression of apoptosis in multicellular organisms was established in studies of a nematode worm with a preposterous name—Caenorhabditis elegans. During its development to a mature individual comprising 1090 cells, C. elegans eliminates precisely 131 cells through apoptosis. Two genes, designated ced-3 and ced-4, induce apoptosis, while a third, ced-9 inhibits its expression [1]. Human counterparts of each of these genes have been identi~ed. The interleukin 1 b converting enzyme family, comprising 11 discrete enzymes that collectively have been called caspases, is the human homolog of ced-3 [2], while the bcl-2 family of proteins is the anti-apoptotic counterpart of ced-9 [3]. A human homolog of ced-4, designated Apaf-1, has recently been described [4]; its function remains to be elucidated. Apoptosis is not a pathologic state, but a normal physiologic process. Indeed, for many cell types, apoptosis appears to be the default program, with the result that the cell will die unless it receives a survival signal from the environment. Such survival signals can be transmitted by soluble mediators such as cytokines, or by adhesive interactions between the cell and its adjacent matrix [5,6]. Apoptosis in human cells represents a balance between the expression of proand anti-apoptotic genes, and both excessive and inadequate expression of apoptosis can cause human disease. The human immunode~ciency virus induces T cell apoptosis, producing the profound lymphopenia and enhanced susceptibility to opportunistic infection that is characteristic of AIDS [7], while the apoptotic death of neurons has been shown to be important in a variety of neurodegenerative disorders [8]. On the other hand, failure of expression of lymphocyte apoptosis contributes to the pathogenesis of autoimmune disease [9], and exaggerated in_ammation in patients with burn injury [10] or the systemic in_ammatory response syndrome [11] is associated with prolonged neutrophil survival, consequent to the inhibition of a constitutively-expressed cell death program. In this issue of Sepsis, seven investigators who have contributed to our growing understanding of apoptosis review its role in the pathogenesis of the sequelae of systemic in_ammation. Carmody and Cotter review the molecular events and intracellular mechanisms of apoptosis [12], while Slee and colleagues discuss the role played by the caspase cascade of pro-apoptotic enzymes in the execution of the apoptotic program [13]. Excessive expression of apoptosis can result in acute organ injury, and Bombeck and Billiar [14] and Faraco and co-workers [15] highlight the importance of apoptosis in the pathogenesis of hepatic and renal failure respectively. Cox discusses the critical role played by the anti-in_ammatory cytokine, interleukin 10, in reversing the delayed apoptosis of in_ammatory neutrophils [16], while Ayala and colleagues review lymphocyte apoptotic death occurring during experimental in_ammation [17]. Finally Fanning underlines the role of the heat shock response in the regulation of apop-