Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis.
Delayed neutrophil apoptosis and overshooting neutrophil activity contribute to organ dysfunction and subsequent organ failure in sepsis. Here, we investigated apoptotic signaling pathways that are involved in the inhibition of spontaneous apoptosis in neutrophils isolated from major trauma patients with uneventful outcome as well as in those with sepsis development. DNA fragmentation in peripheral blood neutrophils showed an inverse correlation with the organ dysfunction at d 10 after trauma in all patients, supporting the important role of neutrophil apoptosis regulation for patient's outcome. The expression of the antiapoptotic Bcl-2 protein members A1 and Mcl-1 were found to be diminished in the septic patients at d 5 and d 10 after trauma. This decrease was also linked to an impaired intrinsic apoptosis resistance, which has been previously shown to occur in neutrophils during systemic inflammation. In patients with sepsis development, delayed neutrophil apoptosis was found to be associated with a disturbed extrinsic pathway, as demonstrated by reduced caspase-8 activity and Bid truncation. Notably, the expression of Dad1 protein, which is involved in protein N-glycosylation, was significantly increased in septic patients at d 10 after trauma. Taken together, our data demonstrate that neutrophil apoptosis is regulated by both the intrinsic and extrinsic pathway, depending on patient's outcome. These findings might provide a molecular basis for new strategies targeting cell death pathways in apoptosis-resistant neutrophils during systemic inflammation.
Department of Trauma and Hand Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.
Adnana
A
Paunel-Görgülü
Tamara
T
Kirichevska
Tim
T
Lögters
Joachim
J
Windolf
Sascha
S
Flohé
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053938:DNA Fragmentation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009104:Multiple Trauma / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009504:Neutrophils / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C096816:BCL2-related protein A1; C083331:DAD1 protein, human; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053181:Caspase 8