title: Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis.
abstract: OBJECTIVE
  Sepsis remains an unresolved clinical problem. Therapeutic strategies focusing on inhibition of neutrophils (polymorphonuclear neutrophils) have failed, which indicates that a more detailed understanding of the underlying pathophysiology of sepsis is required. Polymorphonuclear neutrophil activation and chemotaxis require cellular adenosine triphosphate release via pannexin-1 channels that fuel autocrine feedback via purinergic receptors. In the current study, we examined the roles of endogenous and systemic adenosine triphosphate on polymorphonuclear neutrophil activation and host defense in sepsis.
  
  
  METHODS
  Prospective randomized animal investigation and in vitro studies.
  
  
  METHODS
  Preclinical academic research laboratory.
  
  
  METHODS
  Wild-type C57BL/6 mice, pannexin-1 knockout mice, and healthy human subjects used to obtain polymorphonuclear neutrophils for in vitro studies.
  
  
  METHODS
  Wild-type and pannexin-1 knockout mice were treated with suramin or apyrase to block the endogenous or systemic effects of adenosine triphosphate. Mice were subjected to cecal ligation and puncture and polymorphonuclear neutrophil activation (CD11b integrin expression), organ (liver) injury (plasma aspartate aminotransferase), bacterial spread, and survival were monitored. Human polymorphonuclear neutrophils were used to study the effect of systemic adenosine triphosphate and apyrase on chemotaxis.
  
  
  RESULTS
  Inhibiting endogenous adenosine triphosphate reduced polymorphonuclear neutrophil activation and organ injury, but increased the spread of bacteria and mortality in sepsis. By contrast, removal of systemic adenosine triphosphate improved bacterial clearance and survival in sepsis by improving polymorphonuclear neutrophil chemotaxis.
  
  
  CONCLUSIONS
  Systemic adenosine triphosphate impairs polymorphonuclear neutrophil functions by disrupting the endogenous purinergic signaling mechanisms that regulate cell activation and chemotaxis. Removal of systemic adenosine triphosphate improves polymorphonuclear neutrophil function and host defenses, making this a promising new treatment strategy for sepsis.
authors.affiliation: 1Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 2Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China. 3Ludwig Boltzmann Institute for Traumatology, Lorenz Böhler Unfallkrankenhaus, Vienna, Austria.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Li
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.forename: Laura
authors.initials: L
authors.lastname: Staudenmaier
authors.forename: Albert
authors.initials: A
authors.lastname: Lee
authors.forename: Jingping
authors.initials: J
authors.lastname: Zhang
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology*; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D013498:Suramin / Q000494:pharmacology
chemical_list: D013498:Suramin; D000255:Adenosine Triphosphate; D001081:Apyrase