Role of xanthine oxidase and reactive oxygen intermediates in LPS- and TNF-induced pulmonary edema.
We studied the role of reactive oxygen intermediates (ROI) in lipopolysaccharide (LPS)-induced pulmonary edema. LPS treatment (600 micrograms/mouse, IP) was associated with a marked induction of the superoxide-generating enzyme xanthine oxidase (XO) in serum and lung. Pretreatment with the antioxidant N-acetylcysteine (NAC)--1 gm/kg orally, 45 minutes before LPS--or with the XO inhibitor allopurinol (AP)--50 mg/kg orally at -1 hour and +3 hours--was protective. On the other hand nonsteroidal antiinflammatory drugs (ibuprofen, indomethacin, and nordihydroguaiaretic acid) were ineffective. These data suggested that XO might be involved in the induction of pulmonary damage by LPS. However, treatment with the interferon inducer polyriboinosylic-polyribocytidylic acid, although inducing XO to the same extent as LPS, did not cause any pulmonary edema, indicating that XO is not sufficient for this toxicity of LPS. To define the possible role of cytokines, we studied the effect of direct administration of LPS (600 micrograms/mouse, IP), tumor necrosis factor (TNF, 2.5 or 50 micrograms/mouse, IV), interleukin-1 (IL-1 beta, 2.5 micrograms/mouse, IV), interferon-gamma (IFN-gamma, 2.5 micrograms/mouse, IV), or their combination at 2.5 micrograms each. In addition to LPS, only TNF at the highest dose induced pulmonary edema 24 hours later. LPS-induced pulmonary edema was partially inhibited by anti-IFN-gamma antibodies but not by anti-TNF antibodies, anti-IL-1 beta antibodies, or IL-1 receptor antagonist (IL-1Ra).
Faggioni
R
R
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Gatti
S
S
Demitri
M T
MT
Delgado
R
R
Echtenacher
B
B
Gnocchi
P
P
Heremans
H
H
Ghezzi
P
P
D000111:Acetylcysteine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D007371:Interferon-gamma / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000493:Allopurinol; D007371:Interferon-gamma; D014969:Xanthine Oxidase; D000111:Acetylcysteine