title: Impaired erythropoiesis after haemorrhagic shock in mice is associated with erythroid progenitor apoptosis in vivo.
abstract: OBJECTIVE
  Multiply traumatised patients often suffer from blood loss and from subsequent therapy-resistant anaemia, possibly mediated by apoptosis, necrosis, or humoral factors. Therefore, the underlying mechanisms were investigated in bone marrow (BM) and peripheral blood in a murine resuscitated haemorrhagic shock (HS) model.
  
  
  METHODS
  In healthy male mice, pressure-controlled HS was induced for 60 min. The BM was analysed for Annexin-V, 7-amino-actinomycin D, apoptotic enzymes (caspases-3/7, -8, and -9), expression of death receptors (CD120a, CD95), mitochondrial proteins (Bax, Bcl-2, Bcl-x), as well as erythropoietin (EPO) receptor (EPO-R). Blood cell count, peripheral EPO, and tumour necrosis factor-alpha response were additionally monitored.
  
  
  RESULTS
  Twenty-four and 72 h after HS, EPO and EPO-R were strongly up-regulated in peripheral blood and BM, respectively. Decreasing numbers of erythroid progenitors in BM after HS correlated with significant apoptotic changes confirmed by increased caspases-3/7, -8, -9 activity in total BM, death receptor CD95 and CD120a expression on erythroid progenitors, and down-regulated mitochondrial Bcl-2 expression in total BM. Erythroid progenitors in peripheral blood were found to be increased after 72 h.
  
  
  CONCLUSIONS
  Despite the massive EPO response and up-regulation of EPO-R, BM erythroblasts (EBs) decreased. This could be due to deficient maturation of erythroid progenitors. Furthermore, the increased intrinsic and extrinsic apoptosis activation suggests programmed death of erythroid progenitors. We propose that both apoptosis and negatively regulated erythropoiesis contribute to BM dysfunction, while erythroid progenitor egress plays an additional role.
authors.affiliation: Centre for Trauma and Reconstructive Surgery, Charité- Campus Benjamin Franklin, Berlin, Germany. yohan.robinson@charite.de
authors.forename: Y
authors.initials: Y
authors.lastname: Robinson
authors.forename: A
authors.initials: A
authors.lastname: Matenov
authors.forename: S K
authors.initials: SK
authors.lastname: Tschöke
authors.forename: A
authors.initials: A
authors.lastname: Weimann
authors.forename: A
authors.initials: A
authors.lastname: Oberholzer
authors.forename: W
authors.initials: W
authors.lastname: Ertel
authors.forename: A
authors.initials: A
authors.lastname: Hostmann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D017304:Annexin A5; D061945:Caspase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D020169:Caspases