apoptosis is a tightly regulated process by which cells orchestrate their own dismantling and disposal in an orderly and noninflammatory manner . apoptosis is critical for homeostasis , development and  as highlighted by recent work from giamarellos - bourboulis and colleagues   ( presented in this issue )  for regulation of inflammation and immune cell function . since its first description in 1972 there has been an explosion of literature on this topic . a pubmed search for ' apoptosis ' yields over 100,000 citations . a question when faced with such a number is coincidentally the same as that raised by giamarellos - bourboulis and colleagues ; when is enough apoptosis , enough ? sepsis and septic shock represent an over - exuberant host response to an infectious insult . neutrophils , monocytes and tissue macrophages play key roles in the initial reaction and release a variety of cytokines to marshal the immune response . once the threat is contained and/or the adaptive immune response is awakened , the innate immune cells are downregulated and must be disposed of in a timely and noninjurious manner because some of them are proverbial ' ticking time bombs ' . it has been suggested that dysregulated apoptosis may play a role in increasing the duration and/or severity of the systemic response to sepsis . clearly , monocytes and macrophages can contribute to inflammation simply by ' hanging around ' longer with the opportunity to release their cytotoxic products that damage host cells . additionally , there is evidence that phagocytosis of apoptotic cells leads to active elaboration of anti - inflammatory signals . thus , reduced apoptosis may contribute to inflammation in a number of ways , with the end result being that the host immune response contributes more to damaging the host than to protecting it . it is important to note that apoptosis of structural cells such as endothelium or epithelium in systemic inflammatory response syndrome is associated with disrupted organ function . furthermore , lymphocyte apoptosis is associated with a poor outcome in septic shock , presumably because these cells are important regulators of the immune response and coordinate the body 's response to infection . giamarellos - bourboulis and coworkers   add to this literature and present evidence that early monocyte apoptosis confers a survival advantage in sepsis related to ventilator - associated pneumonia . their study group of patients was divided into those with low ( < 50% ) and high ( > 50% ) rates of monocyte apoptosis when tested on day 1 . forty - nine per cent ( 28 out of 57 ) of those with low apoptosis died versus only 15% ( 5 out of 33 ) of those with high degrees of monocyte apoptosis . this is a remarkable finding , and theirs is one of the first studies to correlate monocyte apoptosis with survival in sepsis . however , some questions arise from these observations . first , is monocyte apoptosis in the study simply a marker for another more proximate factor that is causally associated with mortality ? the authors note that there is a difference in the incidence of bacteraemia between the low and high apoptosis groups but they do not discuss any other parameters . although this group of 90 patients is as homogenous as one can except in a study of sepsis , there are differences between patients that could contribute to mortality . thus , demographic factors ( age , sex ) , illness severity ( acute physiology and chronic health evaluation ii score , sequential organ failure assessment score ) and other comorbid conditions ( trauma , diabetes , medications , etc . ) may be confounding variables if differences exist between the low and high apoptosis groups . second , percentage apoptosis changed over the 7 days during which blood was collected , and so those patients assigned to the low group may at times have had more than 50% apoptosis and vice versa . timing of apoptosis is sure to be important ( theoretically , too much too early may be associated with a poor outcome , as would too little too late ) . duration of illness before enrolment in this study may introduce enough variability to make timing difficult to determine . one possibility , mentioned by the authors , is a decreased release of proinflammatory cytokines by monocytes undergoing apoptosis . however , of the serum cytokines measured ( intereukin-6 , interleukin-8 and tumour necrosis factor- ) no correlation with survival was noted . this is a critical issue if we hope to modulate this process to the advantage of patients . finally , there are a variety of technical considerations in measuring apoptosis in peripheral blood monoctyes that introduce uncertainty into the measurement . the recovery of apoptotic monocytes may not be complete in a ficoll density gradient because cell density is altered by apoptosis . also , healthy monocytes may ingest apoptotic cells and through membrane transfer subsequently stain falsely positive for annexin v. ultimately , it may be the responses of monocytes that have already extravasated from the blood into the tissues that is most relevant to the outcome of sepsis , and this was not measured in the study . given these points , it is too soon to say with certainty that increased early monocyte apoptosis confers a survival advantage in the context of sepsis . however , the study by giamarellos - bourboulis and coworkers is an important first step in trying to make sense of a complicated and fundamentally important process . at the very least , this assay of monocyte apoptosis may conceivably be used as a prognostic tool , especially if it is combined with other factors in a multivariate model .
apoptosis is of pivotal importance in the pathogenesis of sepsis . 
 depending on the cell type involved and the time point of the disease process , apoptosis may be linked to either a good or a bad outcome . 
 work presented in this issue by giamarellos - bourboulis and coworkers suggests that an early increase in the apoptosis of blood monocytes is associated with improved survival in patients with varying degrees of sepsis . 
 although the mechanism by which monocyte apoptosis influences the outcome of sepsis can not be determined by this study , these observations represent an important advance in our understanding of this complicated disease process .