Nitric oxide (NO) is produced by inducible
NO synthase (iNOS) after LPS stimulation, and reacts with
superoxide to form
peroxynitrite. We hypothesize that in LPS-induced
lung injury, NO generated by iNOS plays a key role through the formation of
peroxynitrite. We developed an
acute lung injury dog model by injecting LPS, and examined the effects of selective iNOS inhibitors,
aminoguanidine (AG) and
S-methylisothiourea sulfate (SMT), on the LPS-induced
lung injury. At 24 h after LPS injection, arterial
oxygen tension and mean arterial pressure decreased, and shunt ratio and
lung wet-to-dry weight ratio increased. On histology, the LPS group had marked neutrophil infiltration and widening of the 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 gas exchange, hemodynamics, and wet-to-dry weight ratio. On histology, AG and SMT treatments markedly suppressed
lung injury, iNOS
protein, and
nitrotyrosine production. We conclude that NO released by iNOS may play a critical role in the pathogenesis of LPS-induced
acute lung injury. This study suggests that iNOS inhibitors may have potential in the treatment of LPS-induced
acute respiratory distress syndrome.