Characterization of the phase dependent pulmonary response following irritant inhalation exposure to nitrogen-dioxide gas
Description
Nitrogen dioxide (NO$\sb2$), the most toxic of the oxides of nitrogen, causes free radical, oxidative damage in the lower lung. The present study utilized NO$\sb2$ to fingerprint the biochemical reaction of the pulmonary compartment to oxidative damage and to correlate this with histopathology following acute (1 hr) and subacute (4 hr/day $\times$ 5 days) exposures to NO$\sb2$. Acute exposure to NO$\sb2$ produced dose-dependent immediate increases in the nonenzymatic parameters of pulmonary protein content, protease inhibitor activity and lung weight. The enzymatic activities of lactate dehydrogenase (LDH), choline kinase and beta-glucuronidase were elevated by two days following acute exposure. All of the above parameters were elevated following subacute exposure, however, nonenzymatic manifestations were attenuated with respect to enzymatic alterations. Hydroxyurea-induced granulocytopenia attenuated the increases in activities of LDH and beta-glucuronidase following acute, but not subacute exposures. This implies a plurality of exposure pattern dependent sources for these enzymes. Cycloheximide-induced protein synthesis inhibition decreased the LDH and beta-glucuronidase response to NO$\sb2$ without altering the increases in protein content or protease inhibitor activity It can be concluded from these studies that the pulmonary response to oxidative damage produced by NO$\sb2$ can be divided into three distinct, overlapping phases; i.e. exudative, proliferative and tolerant phases. The exudative phase occurs immediately upon exposure to NO$\sp2$ and is characterized by dead and dying cells, edema and some leukocyte influx corresponding to an increase in the nonenzymatic parameters of protease inhibitor activity, protein content and lung weight. The damage progresses until the lung can mount a significant repair response in the proliferative phase. At this point the lung is severely damaged as indicated by the presence of edema, areas of alveolar collapse and influx of leukocytes. The enzymatic parameters are also elevated suggestive of a lung trying to reestablish homeostasis. Subsequently, the lung enters a tolerant phase during which the inflammation observed following acute exposure to NO$\sb2$ is diminished while the lung's metabolism remains elevated