title: Extracellular ATP drives systemic inflammation, tissue damage and mortality.
abstract: Systemic inflammatory response syndromes (SIRS) may be caused by both infectious and sterile insults, such as trauma, ischemia-reperfusion or burns. They are characterized by early excessive inflammatory cytokine production and the endogenous release of several toxic and damaging molecules. These are necessary to fight and resolve the cause of SIRS, but often end up progressively damaging cells and tissues, leading to life-threatening multiple organ dysfunction syndrome (MODS). As inflammasome-dependent cytokines such as interleukin-1β are critically involved in the development of MODS and death in SIRS, and ATP is an essential activator of inflammasomes in vitro, we decided to analyze the ability of ATP removal to prevent excessive tissue damage and mortality in a murine LPS-induced inflammation model. Our results indeed indicate an important pro-inflammatory role for extracellular ATP. However, the effect of ATP is not restricted to inflammasome activation at all. Removing extracellular ATP with systemic apyrase treatment not only prevented IL-1β accumulation but also the production of inflammasome-independent cytokines such as TNF and IL-10. In addition, ATP removal also prevented systemic evidence of cellular disintegration, mitochondrial damage, apoptosis, intestinal barrier disruption and even mortality. Although blocking ATP receptors with the broad-spectrum P2 purinergic receptor antagonist suramin imitated certain beneficial effects of apyrase treatment, it could not prevent morbidity or mortality at all. We conclude that removal of systemic extracellular ATP could be a valuable strategy to dampen systemic inflammatory damage and toxicity in SIRS.
authors.affiliation: 1] Inflammation Research Center, VIB, Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Cauwels
authors.affiliation: 1] Inflammation Research Center, VIB, Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Rogge
authors.affiliation: 1] Inflammation Research Center, VIB, Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Vandendriessche
authors.affiliation: Department of Pharmacology and Chemical Biology and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shiva
authors.affiliation: 1] Inflammation Research Center, VIB, Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Brouckaert
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001081:Apyrase / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins; D005260:Female; D006868:Hydrolysis; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D013498:Suramin / Q000494:pharmacology; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004731:Endotoxins; D058847:Inflammasomes; D018836:Inflammation Mediators; D058919:Purinergic P2 Receptor Antagonists; D013498:Suramin; C044101:endotoxin, Escherichia coli; D000255:Adenosine Triphosphate; D001081:Apyrase