ABSTRACT
During early postnatal alveolar formation, the lung tissue of rat pups undergoes a physiological remodeling involving apoptosis of distal lung cells. Exposure of neonatal rats to severe hyperoxia (≥95% O(2)) both arrests lung growth and results in increased lung cell apoptosis. In contrast, exposure to moderate hyperoxia (60% O(2)) for 14 days does not completely arrest lung cell proliferation and is associated with parenchymal thickening. On the basis of similarities in lung architecture observed following either exposure to 60% O(2), or pharmacological inhibition of physiological apoptosis, we hypothesized that exposure to 60% O(2) would result in an inhibition of physiological lung cell apoptosis. Consistent with this hypothesis, we observed that the parenchymal thickening induced by exposure to 60% O(2) was associated with decreased numbers of apoptotic cells, increased expressions of the antiapoptotic regulator Bcl-xL, and the putative antiapoptotic protein survivin, and decreased expressions of the proapoptotic cleaved caspases-3 and -7. In summary, exposure of the neonatal rat lung to moderate hyperoxia results in an inhibition of physiological apoptosis, which contributes to the parenchymal thickening observed in the resultant lung injury.
Subject(s)
Apoptosis/drug effects , Lung Injury/chemically induced , Lung Injury/pathology , Oxygen/pharmacology , Signal Transduction/drug effects , Air , Animals , Animals, Newborn , Blotting, Western , Caspase 3/metabolism , Cell Count , Cell Death/drug effects , Female , Immunohistochemistry , Lung/drug effects , Lung/enzymology , Lung/pathology , Rats , Rats, Sprague-Dawley , Staurosporine/pharmacologyABSTRACT
IL-1 beta, a proinflammatory cytokine, may contribute to the development of the chronic neonatal lung injury, bronchopulmonary dysplasia. Chronic neonatal lung injury was induced in rats, by exposure to 60% O2 for 14 d from birth, to determine whether pulmonary IL-1 expression was up-regulated and, if so, whether a daily s.c. IL-1 receptor antagonist injections would be protective. Exposure to 60% O2 for 14 d caused pulmonary neutrophil and macrophage influx, increased tissue fraction and tyrosine nitration, reduced VEGF-A and angiopoietin-1 expression, and reduced small vessel (20-65 microm) and alveolar numbers. Lung IL-1 alpha and -1 beta contents were increased after a 4-d exposure to 60% O2. IL-1 receptor antagonist treatment attenuated the 60% O2-dependent neutrophil influx, the increased tissue fraction, and the reduced alveolar number. Treatment did not restore VEGF-A or angiopoietin-1 expression and only partially attenuated the reduced vessel number in 60% O2-exposed pups. It also caused a paradoxical increase in macrophage influx and a reduction in small vessels in air-exposed pups. We conclude that antagonism of IL-1-mediated effects can, in major part, protect against lung injury in a rat model of 60% O2-induced chronic neonatal lung injury.
