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ARTICLE: Patrik Lassus, Irmeli Nupponen, Anneli Kari, Maija Pohjavuori, and Sture Andersson Early Postnatal Dexamethasone Decreases Hepatocyte Growth Factor in Tracheal Aspirate Fluid From Premature Infants Pediatrics 2002; 110: 768-771 [Abstract] [Full text] [PDF]

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Effects of early dexamethasone therapy on pulmonary mediators in preterm infants

Giovanni VENTO, Piero G. Matassa, Franco Ameglio, Ettore Capoluongo, Luca Tortorolo, and Costantino Romagnoli   (15 October 2002)

Effects of early dexamethasone therapy on pulmonary mediators in preterm infants 15 October 2002
Giovanni VENTO, MD Division of Neonatology - Catholic University of Rome, Piero G. Matassa, Franco Ameglio, Ettore Capoluongo, Luca Tortorolo, and Costantino Romagnoli Send letter to journal: Re: Effects of early dexamethasone therapy on pulmonary mediators in preterm infants vento{at}rm.unicatt.it Giovanni VENTO, et al.	Dear Editor, the recent interesting publication by Lassus et al.1 concerns the effects of early Dexamethasone (DEX) treatment on vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in tracheal aspirate fluid (TAF) from premature infants. This study shows that the VEGF/IgA-SC ratios increase during the study period, from the postnatal days 1-2 to the days 5-7, with no significant differences between DEX or control groups. In addition, a significant reduction of the TAF HGF/IgA-SC ratios was observed in treated infants as compared with untreated patients, even if there was little if any significant variation during the study period. This reduction may participate in the suppressing effect of dexamethasone on lung development. In a previous work,2 the effect of early postnatal steroid administration on three fibrogenic cytokines, namely transforming growth factor- &#61538;1 (TGF-&#61538;1), basic fibroblast growth factor (FGF) and VEGF, was studied by our group on similar (even if more premature) patients, with similar dexamethasone schedule and doses (the only difference being the age at starting therapy: 4th day of life in our study as compared with 12- 24 h of life in the Lassus study). In particular, pulmonary epithelial lining fluid (ELF) VEGF levels, calculated by means of the urea method both in TAF and serum, significantly increased in the control group [6.96 (3.8-28.72) ng/ml – median (range) - at time 0, on the 4th day of life, and 19.5 (5.06-58.6) ng/ml 48 h later (p<0.05)], while no significant change was found in the DEX group [13.47 (7.48-25.28) ng/ml before and 13.52 (4.5-39.86) ng/ml two days after treatment]. ELF TGF- &#61538;1 levels showed a similar profile: in fact they increased during the study period in untreated subjects (p<0.05), similarly to the ELF VEGF concentrations, while a significant fall (p<0.05) in the ELF TGF-&#61538;1 amounts was observed in DEX-treated neonates. The similarity observed between the behaviour of VEGF and TGF-&#61538;1 was also confirmed by the significant correlation found between their concentrations (r=0.51, p=0.001, N-1=39). Moreover, three subjects in the control group (30%) developed severe bronchopulmonary dysplasia (BPD), but none in the treated group. Interestingly, their TGF-&#61538;1 values, recorded on day 2 after treatment, were significantly higher (p<0.05) than those of the subjects with mild BPD (N=11) or without BPD (N=6) The VEGF/IgA-SC ratio behaviour in the study by Lassus et al.1 is surprising. In fact it has been already reported that VEGF expression is downregulated in vitro by steroids in pulmonary fibroblasts and in pulmonary vascular smooth cells.3,4 On the other hand, in vivo, dexamethasone treatment increase VEGF mRNA expression in developing mouse lung, 5 and in newborn rabbits recovering from experimental lung injury, repair of microvascular endothelium correlates with increased expression of VEGF in alveolar epithelial cells.6 The similar VEGF values observed in the study groups by Lassus et al. disagree with the significant difference in the incidence of BPD between treated and untreated infants as well as with the assertion that lower VEGF in TAF are in association with development of BPD. Certainly, despite some controversial literature data, VEGF plays a crucial role in vascular development, and therefore VEGF reduced levels observed in our study could be interpreted as impaired micro vascular repair of lung injury. Nevertheless, recently it has also been demonstrated that activated human neutrophils, which play a central role in the development of chronic lung disease of prematurity, express VEGF:7 therefore their production may be central to the classic acute phase response to injury and chemo-attraction of other leukocytes towards the injury source. In this way, the abolition of a spontaneous VEGF increase observed in treated infants could be interpreted as a “positive” effect of dexamethasone. Whether or not the VEGF discrepancies between our and Lassus data may be due to the use of the cytokine/IgA-SC ratio or to the other differences in the patients' characteristics needs to be clarified. In their publication, Lassus et al.1 reported lower HGF in TAF from preterm infants who received dexamethasone as compared with control ones. They also suggested that “dexamethasone-through its effect on pulmonary HGF-may have adverse influence on pulmonary development and on repair of acute injury in preterm lung”. Surprisingly they also reported a significant reduction of BPD in treated infants as compared with control infants (7% vs. 47%, respectively, p<0.01). We are puzzled over this contradiction. The arising concerns about the short and long term side effects of the postnatal dexamethasone administration to treat and/or prevent BPD of prematurity should persuade all us to step up the studies on this field. Consequently, elucidating the possible mechanisms involved both in the development of BPD and in the action of steroids and defining which cytokines may be involved, may be crucial in preserving the beneficial effects and reducing short and long-term side effects of postnatal steroid administration. References 1) Lassus P, Nupponen I, Kari A, Pohiavuori M, Andersson S. Early postnatal dexamethasone decreases Hepatocyte Growth Factor in tracheal aspirate fluid from premature infants. Paediatrics. 2002;110:768-771 2) Vento G, Matassa PG, Ameglio F, Capoluongo E, Tortorolo L, Romagnoli C. Effects of early dexamethasone therapy on pulmonary fibrogenic mediators and respiratory mechanics in preterm infants. Eur Cytokine Netw. 2002;13(2) :207-214 3) Klekamp JG, Jarzecka K, Hoover RL, Summar ML, Redmond N, Perkett EA. Vascular endothelial growth factor is expressed in ovine pulmonary vascular smooth muscle cells in vitro and regulated by hypoxia and dexamethasone. Pediatr Res. 1997;42:744-749 4) Nauck M, Roth M, Tamm M et al. Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol. 1997;16:398-406 5) Bhatt AJ, Amin SB, Chess PR, Watkins RH, Maniscalco WM. Expression of vascular endothelial growth factor and Flk-1 in developing and glococorticoid-treated mouse lung. Pediatr Res. 2000;47:606-613. 6) Maniscalco WM, Watkins RH, Finkelstein JN, Campbell MH. Vascular endothelial growth factor mRNA increases in alveolar epithelial cells during recovery from oxygen injury. Am J Respir Cell Mol Biol. 1995;13:377 -386. 7) Webb NJ, Myers CR, Watson CJ, Bottomley MJ, Brenchley PE. Activated human neutrophils express vascular endothelial growth factor (VEGF). Cytokine. 1998;10:254-257 Giovanni Vento, Piero Giuseppe Matassa, Franco Ameglio*, Ettore Capoluongo**, Luca Tortorolo, Costantino Romagnoli Division of Neonatology, Policlinico “A. Gemelli”, Università Cattolica S. Cuore, Largo A. Gemelli, 8 00168, Rome, Italy Laboratory of Clinical Pathology, General Hospital “S. Giovanni Calibita” Fatebenefratelli, Rome, Italy and ** Laboratory of Clinical Pathology, Immacolata Hospital, Università Cattolica S. Cuore, Celano (AQ), Italy.