title: Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung.
abstract: The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.
authors.forename: G S
authors.initials: GS
authors.lastname: Worthen
authors.forename: C
authors.initials: C
authors.lastname: Haslett
authors.forename: A J
authors.initials: AJ
authors.lastname: Rees
authors.forename: R S
authors.initials: RS
authors.lastname: Gumbay
authors.forename: J E
authors.initials: JE
authors.lastname: Henson
authors.forename: P M
authors.initials: PM
authors.lastname: Henson
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D002199:Capillary Permeability / Q000187:drug effects*; D002630:Chemotactic Factors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D016209:Interleukin-8; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000648:ultrastructure; D008854:Microscopy, Electron; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors
chemical_list: D000418:Albumins; D002630:Chemotactic Factors; D016209:Interleukin-8; D008070:Lipopolysaccharides; D009588:Nitrogen Mustard Compounds; D009842:Oligopeptides; C024998:N-formylnorleucyl-leucyl-4-phenylalanine