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Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis.
- Source :
-
Molecular medicine (Cambridge, Mass.) [Mol Med] 2012 May 09; Vol. 18, pp. 325-35. Date of Electronic Publication: 2012 May 09. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Adult
Aged
Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins metabolism
Caspase 8 metabolism
DNA Fragmentation
Female
Gene Expression Profiling
Humans
Male
Membrane Proteins genetics
Membrane Proteins metabolism
Middle Aged
Minor Histocompatibility Antigens
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2 genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
Young Adult
bcl-2-Associated X Protein genetics
bcl-2-Associated X Protein metabolism
Apoptosis physiology
Multiple Trauma metabolism
Neutrophils metabolism
Sepsis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-3658
- Volume :
- 18
- Database :
- MEDLINE
- Journal :
- Molecular medicine (Cambridge, Mass.)
- Publication Type :
- Academic Journal
- Accession number :
- 22231730
- Full Text :
- https://doi.org/10.2119/molmed.2011.00380