title: Suicidal erythrocyte death in sepsis.
abstract: Sequelae of sepsis include anemia which presumably results from accelerated clearance of erythrocytes from circulating blood. The underlying mechanisms, however, remained hitherto elusive. Most recent studies disclosed that increased cytosolic Ca2+ activity and ceramide both trigger suicidal erythrocyte death (i.e., eryptosis), which is characterized by lipid scrambling of the cell membrane leading to phosphatidylserine exposure at the erythrocyte surface. Phosphatidylserine exposing erythrocytes may adhere to vascular walls or may be engulfed by macrophages equipped with phosphatidylserine receptors. To explore whether sepsis leads to eryptosis, erythrocytes from healthy volunteers were exposed to plasma of patients suffering from sepsis, or to supernatants from sepsis producing pathogens. Then, phosphatidylserine exposure (annexin V binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence), and ceramide formation (anti-ceramide antibody) were determined by flow cytometry. Challenge of erythrocytes with plasma from the patients but not with plasma from healthy individuals triggered annexin V binding. The effect of patient plasma on erythrocyte annexin V binding was paralleled by formation of ceramide and a significant increase of cytosolic Ca2+ activity. Exposure of erythrocytes to supernatant of pathogens similarly induced eryptosis, an effect correlating with sphingomyelinase activity. The present observations disclose a novel pathophysiological mechanism leading to anemia and derangement of microcirculation during sepsis. Exposure to plasma from septic patients triggers phosphatidylserine exposure leading to adherence to the vascular wall and clearance from circulating blood.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Kempe
authors.forename: Ahmad
authors.initials: A
authors.lastname: Akel
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Tobias
authors.initials: T
authors.lastname: Hermle
authors.forename: Raja
authors.initials: R
authors.lastname: Biswas
authors.forename: Juliana
authors.initials: J
authors.lastname: Muresanu
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrich
authors.forename: Peter
authors.initials: P
authors.lastname: Dreischer
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schumacher
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000328:Adult; D000368:Aged; D017304:Annexin A5 / Q000378:metabolism; D001419:Bacteria; D001772:Blood Cell Count; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002518:Ceramides / Q000096:biosynthesis; D003600:Cytosol / Q000378:metabolism; D004912:Erythrocytes / Q000382:microbiology / Q000473:pathology*; D005260:Female; D006461:Hemolysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010718:Phosphatidylserines / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000473:pathology*
chemical_list: D017304:Annexin A5; D002518:Ceramides; D010718:Phosphatidylserines; D002118:Calcium