The mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration occurring in normal, anesthetized open chest rabbits with prolonged mechanical ventilation (MV) at low lung volume have been investigated. NOe, pH of exhaled vapor condensate, serum prostaglandin E(2), and F(2alpha), tumor necrosis factor (TNF-alpha), PaO(2), PaCO(2), pHa, and lung mechanics were assessed before, during, and after 3-4h of MV at zero end-expiratory pressure (ZEEP), with fixed tidal volume (9 ml kg(-1)) and frequency, as well as before and after 3-4h of MV on PEEP only. Lung histology and wet-to-dry ratio (W/D), and prostaglandin and TNF-alpha in bronchoalveolar lavage fluid (BALF) were also assessed. While MV on PEEP had no effect on the parameters above, MV on ZEEP caused a marked fall (45%) of NOe, with a persistent increase of airway resistance (45%) and lung elastance (12%). Changes in NOe were independent of prostaglandin and TNF-alpha levels, systemic hypoxia, hypercapnia and acidosis, bronchiolar and alveolar interstitial edema, and pH of exhaled vapor condensate. In contrast, there was a significant relationship between the decrease in NOe and bronchiolar epithelial injury score. This indicates that the fall in NOe, which occurs in the absence of an inflammatory response, is due to the epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small airways with MV on ZEEP, and suggests its use as a sign of peripheral airway injury.