Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide.
Mice given lipopolysaccharide (LPS) intravenously developed lung edema, which was maximum after 6 h. Tumor necrosis factor, interleukin 12 (IL-12), IL-6, and interferon-gamma (IFN-gamma) appeared in the serum, and levels of nitrogen oxide (NO) derivatives were increased in serum and bronchoalveolar fluid. Mice pretreated with neutralizing anti-IFN-gamma antibodies had lower serum levels of IFN-gamma, and fewer died. However, levels of other cytokines and NO derivatives as well as lung edema were unchanged. If IFN-gamma and LPS were given together, pulmonary edema was less, but levels of cytokines and NO derivatives in serum were raised, and the mortality was greater. IFN-gamma receptor knockout mice had more edema after LPS, but were less sensitive to the lethal effects. Treatment with anti-IL-12 antibody inhibited IFN-gamma induction and reduced mortality, but had no effect on the lung edema; exogenous IL-12 also failed to affect edema, but boosted serum cytokine levels and increased the mortality. Aminoguanidine, an inhibitor of NO synthase, protected against pulmonary edema, but did not modify the lethal effects of LPS. Clearly, in this model, early pulmonary edema and lethality are not directly related, and induced IFN-gamma has no role in causing early lung edema, but augments other events that result in death.
Heremans
H
H
Laboratory of Immunobiology, Rega Institute, University of Leuven, Faculty of Medicine, Leuven, Belgium. Hubertine.Heremans@rega.kuleuven.ac.be
Dillen
C
C
Groenen
M
M
Matthys
P
P
Billiau
A
A
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D012706:Serratia marcescens; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D006146:Guanidines; D016898:Interferon-alpha; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine