Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction

Objectives: The purpose of this study was to determine whether apoptosis is a major mechanism of cell death in patients with sepsis. The activities of caspase-3 and the antiapoptotic protein, BCL-2, were investigated also. Design: A prospective study of 20 patients who died of sepsis and multiple organ dysfunction was performed. The control group of 16 patients consisted of critically ill, nonseptic patients who were evaluated either prospectiv ely (7) or retrospectively (9), In addition, normal colon sections from sev en patients who had bowel resections were included, Apoptosis was evaluated in hematoxylin and eosin-stained specimens by deoxyuridine triphosphate ni ck end-labeling (TUNEL) and by DNA gel electrophoresis. Setting: Two academic medical centers. Patients: Critically ill patients. Measurements and Main Results:ln septic patients, apoptosis was detected in diverse organs by all three methods with a predominance in lymphocytes and intestinal epithelial cells. Hematoxylin and eosin-stained specimens from septic patients demonstrated at least focal apoptosis in 56.3% of spleens, 47.1% of colons, and 27.7% of ileums. Indirect evidence of lymphocyte apopt osis in septic patients included extensive depletion of lymphocytes in whit e pulp and a marked lymphocytopenia in 15 of 19 patients. Hematoxylin and e osin from nonseptic patients' tissues revealed a low level of apoptosis in one patient only, The TUNEL method increased in positivity with a delay in tissue fixation and was highly positive in many tissues from both septic an d nonseptic patients. Immunohistochemical staining for active caspase-3 sho wed a marked increase in septic vs, nonseptic patients (p < .01), with >25% to 50% of cells being positive focally in the splenic white pulp of six se ptic but in no nonseptic patients Conclusions:We conclude that caspase-3-mediated apoptosis causes extensive lymphocyte apoptosis in sepsis and may contribute to the impaired immune re sponse that characterizes the disorder.