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The mechanisms of the increased tolerance to hyperoxia of neonatal animals of many species is incompletely understood. To investigate the etiology of this difference we compared neutrophi1 entry into the lungs of neonatal and adult rats after hyperoxic exposure. Adult rats were studied after exposure to 298% 0, for 60 h and neonatal rats after 3 and 7 d. Neonatal survival was prolonged compared with that reported for adult rats (77% after 7 d of exposure). In adult rats, there were significant increases in pulmonary neutrophils after 60 h of 0, exposure. In neonatal rats, these changes were not evident after 72 h of exposure, but pulmonary neutrophils increased after 7 d of hyperoxia. Before mortality, pulmonary neutrophils were distributed differently in the age groups. After 7 d of 0, exposure in the neonates, total neutrophil counts in lung tissue (21.92 1 7.29 per cm2 grid) andThe mechanisms of prolonged neonatal tolerance to hyperoxia, which has been noted in the young of many species (1-3), are not completely understood. Species such as the rat, mouse, and rabbit, whose neonates exhibit tolerance, also demonstrate greater induction of antioxidant enzymes than adults in response to hyperoxia (1, 3). This enzyme increase is not seen in the guinea pig and hamster, whose neonates do not exhibit tolerance (1, 3). However, tolerance could also be related to a lower risk of hyperoxic cellular injury to the neonatal lung as a result of diminished oxygen free radical release, a hypothesis which has not been extensively investigated. Ischiropoulos et al. (4) showed lower subcellular superoxide generating capacity in response to 0, in neonatal rats compared with adults. Although the rate of generation of cellular reactive 0, species increases after hyperoxia (5,6), neutrophil accumulation would be expected to augment the total oxidant load presented to pulmonary cells. Neutrophils accumulate in the lung after hyperoxic exposure (7, 8), where they may produce localized damage due to release of toxic oxygen radicals, arachidonic acid metabolites and proteases (9, 10). lung myeloperoxidase (0.085 -t 0.02 Ulmg protein) remained significantly lower than in adults after 60 h of 0, exposure (41.44 5 9.08 per cm2 grid and 0.411 -t 0.085 Ulmg protein, respectively). However, in histologic specimens, 0,-exposed neonates had higher percentages of neutrophils free in the alveolar air space than did adults, corresponding to a trend toward higher neutrophil counts in bronchoalveolar lavage fluid in the neonates. It appears that, in addition to delay in neutrophil influx into the lung, neonatal rats have lowered retention of neutrophils to the alveolar tissue. It is controversial whether neutrophil-mediated responses are necessary for production of acute hyperoxic lung injury. Data implicating neutrophils in the etiology of acute pulmonary oxygen toxicity include neutrophil depletion studies in rabbits, mice, and sheep (1 1-13) and studies correlating diminished inflammatory response with protection from 0,-induced lung injury in...

The pathogenesis of pulmonary oxygen toxicity is postulated to be related in part to neutrophil-mediated injury. This study examined the effect of a monoclonal antibody directed against the CD11a,b,c/CD18 glycoprotein complex (beta 2 leukocyte integrins) on oxygen-induced lung injury. M8, a monoclonal antibody that binds to the beta chain of the guinea pig leukocyte integrins that facilitate neutrophil adherence to vascular endothelium, was injected into adult guinea pigs prior to and during exposure to > 98% oxygen. Control oxygen-exposed animals were injected with a noninhibitory antibody to the CD18 complex or with saline. Survival in oxygen was similar for animals treated with M8 when compared with those treated with saline (102 versus 105 h, respectively, NS). Pulmonary edema as assessed by protein in the supernatant of bronchoalveolar lavage fluid (BALF) was higher in the three groups of oxygen-exposed animals than in the air-exposed groups (p < 0.01), but it did not differ between the M8 antibody treatment group and the other oxygen-exposed groups. M8 antibody treatment did not decrease hyperoxia-induced neutrophil accumulation into the lung as assessed by myeloperoxidase activity (MPO) in lung homogenates or by neutrophil counts in histologic specimens. M8 antibody also did not decrease neutrophil counts or MPO in alveolar lavage fluid, both of which were significantly elevated in all oxygen-exposed groups. These results suggest that hyperoxia-induced neutrophil migration into the lung and acute lung injury occurs by CD18-independent processes in the guinea pig model of pulmonary oxygen toxicity.

ABSI'RACI'. Although prenatal steroid therapy is known to enhance in utero maturation of the surfactant and antioxidant enzyme systems, little is known about the effects of steroids on the antioxidant system after birth. We measured activities of the antioxidant enzymes, catalase, superoxide dismutase, and glutathione peroxidase, in lung homogenates from both preterm and term rat pups after prenatal dexamethasone treatment. Enzyme activities were measured at birth and after exposure to >98% oxygen. Dexamethasone treatment resulted in significantly higher survival of the preterm pups at 24 h (91.3% for dexamethasone versus 57% for saline). In preterm pups, the activities of catalase and superoxide dismutase at birth were higher after dexamethasone treatment (p < 0.05). However, after 24 h of hyperoxic exposure, there were no differences in activities of any of the antioxidant enzymes between the dexamethasone and control groups of prematurely born pups. In term pups, antioxidant enzyme activities did not differ significantly at birth; nor did they differ after 24 to 72 h of hyperoxic exposure in the dexamethasone and control treatment groups. Our results indicate that although prenatal dexamethasone treatment augments survival and catalase and superoxide dismutase activities at birth in preterm rat pups, dexamethasone does not result in altered early postnatal antioxidant enzyme activities after exposure to hyperoxia. (Pediatr Res 33: 177-180, 1993) Abbreviations CAT, catalase SOD, superoxide dismutase GPX, glutathione peroxidase 7 he antioxidant enzyme system serves to protect the organism fiom 02-free radicals that are produced as a result of breathing and metabolizing ambient O?. Production of free radicals increases after exposure to hyperoxic conditions (I), and oxygen tolerance is thought to depend primarily on the capacity to augment antioxidant enzyme activities in response to hyperoxia (2-5). This capacity to increase antioxidant enzymes may account for the greater 0: tolerance of term neonatal animals of several species compared with adults, even though baseline an- tioxidant enzyme activities of the neonate tend to be lower (6. 7). Recent studies in rabbits indicate that, compared with animals born at term, preterms demonstrate both lower 0 2 tolerance and a diminished ability to respond to hyperoxia with increases in antioxidant enzyme activities (8).Activities of the antioxidant enzymes, CAT, SOD. and GPX. increase in the last 10 to 15% of gestation (9-12). It has been demonstrated that prenatal administration of dexamethasone causes not only increased maturation of the surfactant system. but also increases in antioxidant enzyme activities in the fetus (13). However. because augmentation of enzyme activities in response to hyperoxia may be necessary for tolerance. the effect of urenatal dexamethasone on ~ostnatal enzyme resuonses to hyperoxia may be more important than its ability td increase baseline activities in fetal animals.To our knowledge, there is only one preliminary report of antioxidant en...

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