Role of active nitrogen oxide in cell stretch-induced pulmonary alveolar injury.

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When rats were ventilated with a tidal volume of 30 ml/kg body weight and a PEEP of 0 cmH_2O, ventilator-induced lung injury (VILI) was induced, which was characterized by neutrophil infiltration into alveoli and retention of alveolar fluid. Pretreatment with endotoxin (LPS, 1 mg/kg body weight) augmented VILI. Both NO_2 and NO_3 concentrations in broncho-alveolar lavage fluid (BALF) from VILI lungs were significantly higher than those from spontaneous breathing or a tidal volume of 10 ml/kg body weight.Pretreatment with ONO-1714, a specific inducible nitric oxide synthase (iNOS) inhibitor, attenuated VILI in a dose-dependent manner ; both neutrophil count and NO_2/110_3 concentrations in BALF were significantly decreased compared with untreated VILI.Pretreatment with superoxide dismutase (SOD) did not change histopathological findings of VILI significantly, however, both neutrophil count and NO_2/NO_3 concentrations of BALF tended to be reduced compared with untreated VILI.Expression of both iNOS protein and iNOS mRNA were augmented in VILI compared with control lungs.Alveolar type II cells (type II cells) were isolated from rat lungs, and a pressure of 30-50 cmH_2O at a rate of 15 times/min for 3 hours was applied on those type II cells. NO_2/NO_3 concentrations in supernatant of cultured type II cells were significantly elevated in response to pressure load. Frequency of apoptosis of pressure-loaded type II cells was significantly increased and activation of NF-κB was significantly augmented compared with untreated type II cells.Pretreatment of type II cells with ONO-1714 significantly inhibited increment of apoptosis and tended to attenuate activation of NF-κB induced by pressure load.These results indicated that expression of iNOS and subsequent NO_2/NO_3 production were involved in lung injury induced by cell stretch and/or deformity.