INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE PREVENTS LPS-INDUCED ACUTE LUNG INJURY IN DOGS

Nitric oxide (NO) is produced by inducible NO synthase (iNOS) after LP S stimulation, and reacts with superoxide to form peroxynitrite. We hy pothesize that in LPS-induced lung injury, NO generated by iNOS plays a key role through the formation of peroxynitrite. We developed an acu te lung injury dog model by injecting LPS, and examined the effects of selective iNOS inhibitors, aminoguanidine (AG) and S-methylisothioure a sulfate (SMT), on the LPS-induced lung injury, At 24 h after LPS inj ection, arterial oxygen tension and mean arterial pressure decreased, and shunt ratio and lung wet-to-dry weight ratio increased, On histolo gy, the LPS group had marked neutrophil infiltration and widening of t he alveolar septa, On immunohistochemistry, iNOS and nitrotyrosine, a major product of nitration of protein by peroxynitrite, were observed in the interstitium, capillary wall, and neutrophils in the airspaces of the LPS group, Treatments with AG and SMT prevented worsening of ga s exchange, hemodynamics, and wet-to-dry weight ratio, On histology, A G and SMT treatments markedly suppressed lung injury, iNOS protein, an d nitrotyrosine production, We conclude that NO released by iNOS may p lay a critical role in the pathogenesis of LPS-induced acute lung inju ry, This study suggests that iNOS inhibitors may have potential in the treatment of LPS-induced acute respiratory distress syndrome.