title: A ribonucleotide reductase inhibitor reverses burn-induced inflammatory defects.
abstract: Immature myeloid cells have been implicated as a source of postburn inflammation, and the appearance of these cells correlates with enhanced upregulation of hematopoiesis. The role of proliferative cells in postburn immune changes has not been directly tested. Gemcitabine, a ribonucleotide reductase inhibitor, has been shown to deplete proliferative immature myeloid cells in tumor models while sparing mature cells, leading to restored lymphocyte function and tumor regression. We treated burn mice at postburn day 6 (PBD6) with 120 mg/kg gemcitabine. On PBD8, splenocytes were taken and stimulated with LPS, peptidoglycan, or concanavalin A. The blood and spleen cell populations were enumerated by flow cytometry or automated cell counter. In addition, mice treated with gemcitabine were given LPS or infected with Pseudomonas aeruginosa at PBD8, and mortality was monitored. Gemcitabine depleted burn-induced polymorphonuclear leukocytes and inflammatory monocytes without affecting mature F4/80 macrophages. This was accompanied by reduced TNFα, IL-6, and IL-10 production by burn splenocytes. Burn splenocytes stimulated with mitogens exhibited increased nitric oxide production relative to sham mice. In vivo treatment of burn mice with gemcitabine blocked these burn-induced changes without damaging lymphocyte function. Treatment of burn mice with gemcitabine ameliorated burn-induced susceptibility to LPS and infiltration of polymorphonuclear leukocytes into the liver and lung. Finally, gemcitabine treatment blocked the protective effect of burn injury upon P. aeruginosa infection. Our report shows that proliferative cells are major drivers of postburn immune changes and provides evidence that implicates immature myeloid cells in these processes.
authors.affiliation: Shriners Hospital for Children, Cincinnati, Ohio 45229, USA. gnoel@shrinenet.org
authors.forename: Greg
authors.initials: G
authors.lastname: Noel
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Osterburg
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: Laura
authors.initials: L
authors.lastname: James
authors.forename: Lauren
authors.initials: L
authors.lastname: Haar
authors.forename: Nicholas
authors.initials: N
authors.lastname: Giacalone
authors.forename: Ingrid
authors.initials: I
authors.lastname: Thomas
authors.forename: Cora
authors.initials: C
authors.lastname: Ogle
mesh_terms: D000818:Animals; D002056:Burns / Q000188:drug therapy / Q000276:immunology*; D003208:Concanavalin A / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010457:Peptidoglycan / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000150:complications; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000093542:Gemcitabine
chemical_list: C556062:IL10 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D003208:Concanavalin A; D016753:Interleukin-10; D009569:Nitric Oxide; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine