491 Recombinant Human Kgf/Palifermin® as An Alternative to Glucocorticoids- Effects on Pneumocyte Proliferation and Gene Expression in Neonatal Rats

Abstract

Background: Surfactant decreases surface tension of pulmonary air:liquid interfaces. It mainly comprizes characteristic phosphatidylcholine (PC) species and proteins SP-A to -D. Betamethasone used to accelerate “lung maturation” is catabolic, while keratinocyte growth factor (KGF), expressed by fibroblasts, is non-catabolic, acts specifically on type-II-pneumocytes and correlates inversely with bronchopulmonary dysplasia incidence.Aims: To explore the potential of recombinant human KGF (rhKGF, Palifermin®) on neonatal lung development and surfactant metabolism. To contrast rhKGF with betamethasone effects in vivo.Methods: Postnatal rats (d1, d5, d19) were injected with rhKGF (2x5mg/kg), betamethasone (2x1mg/kg) or rhKGF+betamethasone over 48h. Pneumocyte proliferation was detected using bromodeoxyuridine incorporation. Expression of SP-A to -D, adipocyte triglyceride lipase (ATGL), lyso-PC-acyltransferase (LPCAT) and the ATGL activator CGI-58 were measured with PCR.Results: RhKGF, betamethasone and combination treatment increased SP-B expression throughout by +97-117%, +42-51% and +93-309% (P< 0.001), respectively. SP-C was increased by +35-48%, +30- 44% and +74-108% (P< 0.001) after the respective treatments, while SP-A&-D were unchanged in immature lungs. All treatments increased the expression of ATGL (+50-75%), LPCAT (+15-20%) und CGI-58 (+5-10%) (P< 0.05). However, whereas rhKGF effects were accompanied by increased pneumocyte proliferation, betamethasone blocked both basic (d7) and rhKGF-induced (d7+d21) proliferation.Conclusion: Short term medication of neonatal rats with rhKGF/Palifermin® increased the expression of genes relevant for surfactant function and metabolism. Actions were identical or superior to those of betamethasone, with combination treatment exerting maximal effects. However, while betamethasone effects were at the expense of lung anabolism/pneumocyte proliferation, rhKGF enhanced proliferation.