title: Ecto-5'-nucleotidase (CD73) decreases mortality and organ injury in sepsis.
abstract: The extracellular concentrations of adenosine are increased during sepsis, and adenosine receptors regulate the host's response to sepsis. In this study, we investigated the role of the adenosine-generating ectoenzyme, ecto-5'-nucleotidase (CD73), in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury, as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased cleavage of caspase-3 and poly(ADP-ribose) polymerase and increased activation of NF-κB. Septic CD73 KO mice had higher blood urea nitrogen levels and increased cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using α, β-methylene ADP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis.
authors.affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Balázs
authors.initials: B
authors.lastname: Csóka
authors.forename: Balázs
authors.initials: B
authors.lastname: Koscsó
authors.forename: Rachna
authors.initials: R
authors.lastname: Chandra
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Linda F
authors.initials: LF
authors.lastname: Thompson
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Spolarics
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Pál
authors.initials: P
authors.lastname: Gergely
authors.forename: Rolando H
authors.initials: RH
authors.lastname: Rolandelli
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology / Q000378:metabolism*; D000241:Adenosine / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D018925:Chemokines; D015720:5'-Nucleotidase; D000241:Adenosine