title: Primed neutrophils injure rat lung through a platelet-activating factor-dependent mechanism.
abstract: Bacterial lipopolysaccharide (LPS) promotes transient lung neutrophil sequestration. These LPS-primed neutrophils, when stimulated by an N-formyl peptide (FNLP), promote lung injury. We hypothesized that LPS-primed, FNLP-stimulated neutrophils promote lung injury through a platelet-activating factor (PAF)-dependent mechanism. Rats were pretreated with either saline or WEB2170, a PAF receptor antagonist (10 mg/kg po). One hour after pretreatment, rats were administered intraperitoneal LPS (salmonella typhimurium lipopolysaccharide, 500 micrograms/kg) followed 6 hr later by intravenous FNLP (250 micrograms/kg infused over 30 min). Two hours after the initiation of FNLP infusion, rats were sacrificed and assays were performed to measure: (1) lung neutrophil sequestration with myeloperoxidase (MPO) activity; (2) circulating neutrophil activation with nitroblue tetrazolium (NBT) staining, and (3) lung microvascular leak with 125I-albumin flux. We found that lung myeloperoxidase, circulating neutrophil NBT staining, and lung 125I-albumin flux were increased (P less than 0.05) in saline-pretreated LPS/FNLP rats, relative to control. While lung MPO remained increased (P less than 0.05) in WEB2170-pretreated LPS/FNLP rats, circulating neutrophil NBT and lung 125I-albumin flux were decreased (P less than 0.05) relative to those in saline-pretreated rats. We conclude that PAF mediates LPS/FNLP-induced neutrophil activation and lung injury, but is independent from lung neutrophil sequestration. Thus, lung neutrophil sequestration does not inevitably produce lung injury. Rather, neutrophils can accumulate in the lung without causing lung injury if neutrophil activation can be blocked.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: B O
authors.initials: BO
authors.lastname: Anderson
authors.forename: R S
authors.initials: RS
authors.lastname: Poggetti
authors.forename: P F
authors.initials: PF
authors.lastname: Shanley
authors.forename: D D
authors.initials: DD
authors.lastname: Bensard
authors.forename: J M
authors.initials: JM
authors.lastname: Pitman
authors.forename: D W
authors.initials: DW
authors.lastname: Nelson
authors.forename: G J
authors.initials: GJ
authors.lastname: Whitman
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009580:Nitroblue Tetrazolium; D009842:Oligopeptides / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism; D013194:Staining and Labeling; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001381:Azepines; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010972:Platelet Activating Factor; D012709:Serum Albumin; D014230:Triazoles; D009580:Nitroblue Tetrazolium; C024998:N-formylnorleucyl-leucyl-4-phenylalanine; C063964:bepafant; D009195:Peroxidase