title: Reversible lung neutrophil accumulation can cause lung injury by elastase-mediated mechanisms.
abstract: Neutrophils have been implicated in multiple models of end-organ injury. The purposes of this study were to determine whether (1) a sublethal septic insult promotes lung neutrophil accumulation, (2) this pulmonary neutrophil accumulation is reversible, (3) these accumulated neutrophils can be activated to injure lung, and (4) this pulmonary neutrophil accumulation obligates lung injury. Rats were administered low-dose endotoxin, 500 micrograms/kg, intraperitoneally, and at 6 or 12 hours, lungs were harvested and assayed for myeloperoxidase, a marker of neutrophil accumulation, and iodine 125-labeled albumin uptake, a marker of lung injury. A second set of rats were administered low-dose endotoxin and at 6 or 12 hours were given a neutrophil activator formyl-norleucyl-leucyl-phenylalanine (FNLP) 250 micrograms/kg, intravenously. At 8 or 14 hours, lungs were harvested and assayed for 125I-labeled albumin uptake. A third set of rats were administered low-dose endotoxin, and at 5 1/2 hours 30 minutes before FNLP administration, they were given a neutrophil elastase inhibitor, methyoxysuccinyl-L-alanine-L-alanine-L-proline-L-valine-chlorometh yl ketone, 2.5 mg/kg, intraperitoneally. At 6 hours rats were given FNLP, and at 8 hours lungs were harvested and assayed for 125I-labeled albumin uptake. The following results were obtained: (1) low-dose endotoxin caused a transient increase (p less than 0.05) in lung neutrophil accumulation at 6 hours, which was resolved by 12 hours; (2) lung 125I-labeled albumin uptake was unchanged both 6 and 12 hours after isolated low-dose endotoxin administration; (3) neutrophil activation increased (p less than 0.05) lung 125I-labeled albumin uptake when imposed 6 but not 12 hours after low-dose endotoxin administration; and (4) elastase inhibition decreased (p less than 0.05) the lung 125I-labeled albumin uptake promoted by endotoxin and FNLP. We conclude that sublethal endotoxemia causes a reversible lung neutrophil accumulation and that this lung neutrophil accumulation does not obligate lung injury; but activation of these accumulated neutrophils can promote lung injury, and this neutrophil-associated lung injury is mediated in part by neutrophil elastase.
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: J M
authors.initials: JM
authors.lastname: Brown
authors.forename: D D
authors.initials: DD
authors.lastname: Bensard
authors.forename: M A
authors.initials: MA
authors.lastname: Grosso
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.forename: A
authors.initials: A
authors.lastname: Patt
authors.forename: G J
authors.initials: GJ
authors.lastname: Whitman
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D004731:Endotoxins / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D010196:Pancreatic Elastase / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D004731:Endotoxins; D012709:Serum Albumin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C026704:methoxysuccinyl-alanyl-alanyl-prolyl-valine chloromethyl ketone; D009195:Peroxidase; D010196:Pancreatic Elastase