FNLP injures endotoxin-primed rat lung by neutrophil-dependent and -independent mechanisms.
Bacterial lipopolysaccharide (LPS) and an N-formyl peptide, N-formyl-neoleucyl-leucyl-phenylalanine (FNLP), synergistically promote lung injury in rats as measured by 125I-labeled albumin flux. Concomitantly, neutrophils are sequestered in the lung. We hypothesized that LPS-FNLP-induced lung injury is mediated both by neutrophil-dependent and -independent mechanisms. Rats were depleted of circulating and marginating neutrophils with vinblastine. LPS-FNLP-induced lung protein leak was partially decreased in these neutrophil-depleted animals, although a component of lung injury remained. We hypothesized that LPS-FNLP-induced lung injury was also mediated by xanthine oxidase (XO). Rats were fed a tungsten-enriched diet that inactivates molybdenum-dependent oxidase systems. LPS-FNLP-induced lung leak was partially decreased in these animals as well. When tungsten-fed rats were also neutrophil depleted with vinblastine, no increase in 125I-albumin flux was observed in response to LPS-FNLP. In parallel experiments, lungs from vinblastine-pretreated rats were isolated and perfused. FNLP infusion into the LPS-primed, crystalloid-perfused lungs caused increased 125I-albumin flux, which was prevented by oxidase inhibition. We conclude that LPS-FNLP-induced lung injury is both neutrophil mediated and neutrophil independent. The nonneutrophil component of the LPS-FNLP-induced lung injury appears to be pulmonary XO derived and dependent.
Anderson
B O
BO
Department of Surgery, University of Colorado, Denver 80262.
Bensard
D D
DD
Brown
J M
JM
Repine
J E
JE
Shanley
P F
PF
Leff
J A
JA
Terada
L S
LS
Banerjee
A
A
Harken
A H
AH
D000818:Animals; D004032:Diet; D004731:Endotoxins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D010477:Perfusion; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium; D014414:Tungsten / Q000008:administration & dosage; D014747:Vinblastine / Q000494:pharmacology
D004731:Endotoxins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D011506:Proteins; D014747:Vinblastine; C024998:N-formylnorleucyl-leucyl-4-phenylalanine; D009195:Peroxidase; D014414:Tungsten