title: Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury.
abstract: Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5'-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI.
authors.affiliation: Center for Translational Medicine, The Jane and Leonard Korman Lung Center, 1025 Walnut St., College Bldg., Philadelphia, PA 19107. Ross.summer@jefferson.edu.
authors.forename: Dilip
authors.initials: D
authors.lastname: Shah
authors.forename: Freddy
authors.initials: F
authors.lastname: Romero
authors.forename: William
authors.initials: W
authors.lastname: Stafstrom
authors.forename: Michelle
authors.initials: M
authors.lastname: Duong
authors.forename: Ross
authors.initials: R
authors.lastname: Summer
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology / Q000494:pharmacology; D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000903:Antibiotics, Antineoplastic; D018925:Chemokines; D008070:Lipopolysaccharides; D001761:Bleomycin; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase
keywords: acute lung injury; acute respiratory distress syndrome; chemokines; extracellular ATP; neutrophil