ROLE OF XANTHINE-OXIDASE AND REACTIVE OXYGEN INTERMEDIATES IN LPS-INDUCED AND TNF-INDUCED PULMONARY-EDEMA

We studied the role of reactive oxygen intermediates (ROI) in lipopoly saccharide (LPS)-induced pulmonary edema. LPS treatment (600 mu g/mous e, IP) was associated with a marked induction of the superoxide-genera ting enzyme xanthine oxidase (XO) in serum and lung. Pretreatment with the antioxidant N-acetylcysteine (NAC)-1 gm/kg orally, 45 minutes bef ore 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 ant iinflammatory drugs (ibuprofen, indomethacin, and nordihydroguaiaretic acid) were ineffective. These data suggested that XO might be involve d in the induction of pulmonary damage by LPS. However, treatment with the interferon inducer polyriboinosylic-polyribocytidylic acid, altho ugh 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 di rect administration of LPS (600 mu g/mouse, IP), tumor necrosis factor (TNF, 2.5 or 50 mu g/ mouse, IV), interleukin-1 (IL-1 beta, 2.5 mu g/ mouse, IV), interferon-gamma (IFN-gamma, 2.5 mu g/mouse, IV), or their combination at 2.5 mu g each. In addition to LPS, only TNF at the hig hest dose induced pulmonary edema 24 hours later. LPS-induced pulmonar y edema was partially inhibited by anti-IFN-gamma antibodies but not b y anti-TNF antibodies, anti-IL-1 beta antibodies, or IL-1 receptor ant agonist (IL-1Ra).