© 2003 American Thoracic Society
Glucocorticoids in Preterm Infants and Discrepancies of Vascular Endothelial Growth FactorTo the Editor:The importance of elucidating the regulation of vascular endothelial growth factor in the newborn lung and the interference of antenatal and postnatal glucocorticoids with this growth factor recently have been emphasized. Lassus and colleagues (1, 2) repeatedly found no significant differences in the ratios between vascular endothelial growth factor and secretory component of IgA in tracheal aspirate fluid analyzed in dexamethasone-treated or untreated preterm infants. In our experience (3), however, pulmonary levels of vascular endothelial growth factor in epithelial lining fluid significantly increased in the untreated as compared with the dexamethasone-treated group (at similar schedule and dose). In the same samples, transforming growth factor-ß1 levels showed a similar profile, increasing during the study period in the untreated subjects (p < 0.05), whereas a significant decrease (p < 0.05) was observed in treated infants. Moreover, the values of transforming growth factor-ß1 from three untreated subjects (30%), in whom severe bronchopulmonary dysplasia developed, were significantly greater (p < 0.05) than those found in babies with mild or no bronchopulmonary dysplasia. The behavior of vascular endothelial growth factor shown by Lassus and colleagues (1, 2) is surprising. In fact, it has been reported that its expression is downregulated in vitro by steroids in pulmonary fibroblasts (4) even if, in vivo, dexamethasone treatment increases its mRNA expression in developing mouse lung (5) and in newborn rabbits recovering from experimental lung injury. The unchanged values of the cytokine observed in the two study groups by Lassus and colleagues (2) conflict with the significant difference in the incidence of bronchopulmonary dysplasia between treated and untreated infants (2), as well as with the assertion that lower concentrations are associated with bronchopulmonary dysplasia (1, 2). Vascular endothelial growth factor plays a crucial role in vascular development, and the reduction observed in our study could be interpreted as impaired microvascular repair of lung injury, but it has been demonstrated that activated human neutrophils also express this mediator (6). Therefore, its production may be central to the classic acute phase response to injury and chemoattraction of other leukocytes toward the injury source. In this way, the abolition of a spontaneous increase of vascular endothelial growth factor observed in the treated infants in our study could be interpreted as a positive effect of dexamethasone. Clarifying the possible mechanisms involved in both the development of bronchopulmonary dysplasia and the action of steroids may be crucial in preserving the beneficial effects and reducing short- and long-term side effects of postnatal steroid administration.
a Università Cattolica S. Cuore Rome, Italy REFERENCES
From the Authors: We thank Vento and coworkers for their comments on our articles (1, 2). In their letter they raise an interesting question concerning the regulation of pulmonary vascular endothelial growth factor (VEGF) by glucocorticoids. It has been shown by several groups that glucocorticoids inhibit VEGF expression in various cell types in vitro (3–5). However, this effect has not been confirmed in vivo. We found, in our study in preterm infants, no differences in VEGF concentrations between those who received early postnatal dexamethasone and those who did not. However, D'Angio and colleagues (6) showed that, in preterm infants, postnatal dexamethasone was associated with greater pulmonary VEGF levels. In contrast, Vento and colleagues (7) found that postnatal glucocorticoids were associated with lower pulmonary VEGF in preterm infants. The reasons for different results in these three studies remain enigmatic. One possibility is differences in patient materials, for example, with regard to gestational age and morbidity rates. The effect of glucocorticoids on VEGF may also be dose-dependent. The relation among glucocorticoids on VEGF is important, on the one hand because of the frequent, at least antenatal, use of glucocorticoids, on the other hand because VEGF seems to play a crucial role in pulmonary development and in development of bronchopulmonary dysplasia (BPD). Our group has previously shown that pulmonary VEGF levels increase steadily during the first postnatal days, and that an association exists between lower pulmonary VEGF levels and greater incidence of BPD (8). Bhatt and colleagues (9) found, in lung specimens obtained by autopsy in infants dying of BPD, decreased VEGF and Flt-1 expression in association with an arrest of alveolar development and with abnormal capillary development. It has been suggested by Abman (10) that because VEGF participates in normal pulmonary development, a decrease in pulmonary VEGF might interfere with normal alveolarization and participate in the arrest of lung development in infants developing BPD. These data emphasize the importance of elucidating the regulation of VEGF in the newborn lung and the interference of antenatal and postnatal glucocorticoids with this growth factor.
Hospital for Children and Adolescents Helsinki University Central Hospital Helsinki, Finland Acknowledgments P.L. has no declared conflict of interest; S.A. has no declared conflict of interest. REFERENCES
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