EFFECT OF CYCLOOXYGENASE INHIBITORS AND MODULATORS OF CYCLIC-AMP FORMATION ON LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL INFILTRATION IN MOUSE LUNG

1 The adult respiratory distress syndrome (ARDS) is an acute lung infl ammation developed after direct or indirect contact with pathogenic ag ents. In the present study, a mouse model was developed to mimic this condition using aerosolized bacterial lipopolysaccharide (LPS) and to investigate the mechanisms involved in the lung inflammatory response. 2 Inhalation of LPS led to a time and dose-dependent increase in tumo ur necrosis factor-alpha (TNF-alpha) production and neutrophil recruit ment into the bronchoalveolar lavage fluid (BALF) of Balb/c mice. Unde r the same conditions, neutrophil infiltration was also found in the B ALF of the LPS-sensitive mouse strain C3H/HeN, but was absent in the L PS-resistant strain C3H/HeJ. Intranasal administration of murine recom binant TNF-alpha also triggered neutrophil recruitment. 3 One hour aft er inhalation of LPS, half of the maximal level of TNF-alpha was measu red in the BALF but only a few neutrophils were detected at this time. The peak TNF-alpha concentration was reached at 3 h, when the neutrop hil amount started to increase. At 24 h, maximal neutrophil number was found in the BALF and TNF-alpha was no longer present. 4 Pretreatment of mice under different experimental conditions demonstrated that: (a ) cycloheximide almost completely blocks both neutrophil recruitment a nd TNF-alpha production; (b) anti TNF-alpha antibodies block neutrophi l recruitment; (c) indomethacin or aspirin enhance by two fold neutrop hil recruitment; (d) indomethacin significantly increases TNF-alpha pr oduction 1 h after inhalation of LPS; (e) dibutyryl cyclic AMP and pro staglandin E(2) (PGE(2)) block both neutrophil recruitment and TNF-alp ha production. 5 It is concluded that aerosolized LPS in mice triggers an acute lung inflammation which can be used as a potential model of inhalational ARDS and that, strategies leading to the elevation of cyc lic AMP levels in vivo can be effective in modulating LPS-induced TNF- alpha synthesis and neutrophil recruitment.