title: Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis.
abstract: OBJECTIVE
  We sought to determine the influence of thermal (burn) injury with sepsis and norepinephrine on the clonogenic potential and functional cytokine response to lipopolysaccharide (LPS) stimulation in nonmyeloid committed (CD117) and myeloid committed (ER-MP12) bone marrow progenitor cells.
  
  
  BACKGROUND
  We have previously demonstrated that norepinephrine stimulated myelopoiesis after burn injury and sepsis, but the site of this stimulation in monocyte development is unknown. In the present study the influence of norepinephrine on the developmental hierarchy of bone marrow cells after thermal injury and sepsis was determined by assessing the clonogenic potential and LPS-stimulated cytokine responses of mature macrophages derived from CD117 and ER-MP12 bone marrow progenitor cells.
  
  
  METHODS
  Tissue and bone marrow norepinephrine content was ablated by chemical sympathectomy with 6-hydroxydopamine treatment. CD117 and ER-MP12 bone marrow cells were isolated using antibody-linked magnetic microbeads. Clonogenic potential in response to colony-stimulating factors was determined. Both progenitor cell types were differentiated to mature macrophages in vitro and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 cytokine responses to LPS provocation were determined.
  
  
  RESULTS
  The macrophage- and granulocyte-macrophage colony-stimulating factor responsive clonogenic potential was increased with burn sepsis, suggesting an expansion of both progenitor populations. Such increases were greatly reduced with prior depletion of norepinephrine. TNF-alpha and IL-6 cytokine responses to LPS were markedly influenced by the specific progenitor cells involved as well as the injury conditions and the status of norepinephrine prior to injury. In burn sepsis the depletion of norepinephrine resulted in a dramatic decrease in both IL-6 and TNF-alpha production by both progenitor-derived macrophages.
  
  
  CONCLUSIONS
  Depletion of norepinephrine attenuated burn and burn sepsis-induced bone marrow progenitor clonal growth in response to macrophage- and granulocyte-macrophage colony-stimulating factor. Functional phenotypes of bone marrow progenitor-derived macrophages are greatly influenced by norepinephrine and the milieu created by thermal injury and sepsis.
authors.affiliation: Department of Physiology, The Burn and Shock Trauma Institute Loyola University Medical Center Maywood, Illinois, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Cohen
authors.forename: Ravi
authors.initials: R
authors.lastname: Shankar
authors.forename: Julia
authors.initials: J
authors.lastname: Stevenson
authors.forename: Rosaura
authors.initials: R
authors.lastname: Fernandez
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Jones
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000378:metabolism*; D002056:Burns / Q000150:complications / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018952:Antigens, CD34; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019009:Proto-Oncogene Proteins c-kit; D009638:Norepinephrine