Dexamethasone Potentiates Keratinocyte Growth Factor-Stimulated SP-A and SP-B Gene Expression in Alveolar Epithelial Cells

Abstract

Keratinocyte growth factor (KGF, or fibroblast growth factor 7) was previously reported to enhance the synthesis of surfactant in alveolar type II cells. We investigated the possible interactions between KGF and a glucocorticoid, dexamethasone (Dex), on surfactant protein (SP) gene expression. In cultured fetal rat type II cells, KGF and Dex induced greater-than-additive stimulating effects on SP-A and SP-B expressions that were enhanced three-fold and 30-fold, respectively, but had only additive effects on SP-C expression. Using murine lung epithelial (MLE) cells, KGF increased SP-A, SP-B (up to two-fold), and SP-C (up to three-fold) mRNA levels in a dose-dependent way. Dex 10(-9) to 10(-7) M increased SP-A and SP-B mRNA 1.5-fold and SP-C mRNA two-fold. Consistent with type II cell findings, simultaneous treatment by KGF and Dex induced a synergistic increase of SP-A and SP-B transcripts (three-fold and 4.5-fold, respectively), but not of SP-C transcripts. SP-A protein was present in MLE-15 and was increased about three-fold by KGF plus Dex. Expression study of a reporter gene placed under either the SP-A or the SP-B gene regulatory sequences and transfected in MLE-15 cells indicated that the Dex-KGF synergy was achieved mainly through a transcriptional effect for SP-A, and both transcriptional and nontranscriptional effects for SP-B. For the latter, increased mRNA stability was evidenced with the aid of actinomycin D. The Dex-KGF synergy may have potential interest for diseases associated with surfactant deficiency.

Glucocorticoid Regulation of Human Pulmonary Surfactant Protein-B mRNA Stability Involves the 3′-Untranslated Region

“…These results indicate that either murine SP-B mRNA stability is not regulated by DEX or the cells no longer possess this capacity. To date, there are no published reports of the possible effects of DEX on murine SP-B mRNA stability, although there is a report that the addition of DEX plus keratinocyte growth factor (KGF) somewhat increases the stability of murine SP-B mRNA stability (23).…”

Hypoxia-Induced Mitogenic Factor Modulates Surfactant Protein B and C Expression in Mouse Lung

“…A lack of SP-C is associated with respiratory distress syndrome (5,6). Regulation of SP gene expression is multifactorial, involving glucocorticoid hormones (8), retinoic acid (9), fibroblast growth factor (FGF)-2 (10), transforming growth factor-␤ (11), nitric oxide, and keratinocyte growth factor (12).…”

Glucocorticoid action in development

“…Firstly, glucocorticoids promote changes in respiratory epithelial fluid transport [34 • ], from Cl ÿ -dependent fluid secretion (seen earlier in gestation, promoting filling and expansion of the bronchial tree) to Na + and water reabsorption with glucocorticoids up-regulating epithelial sodium channel subunits [35,36], Na + K + ATPase, and specific aquaporins (AQP1 and AQP5) [37,38 • ]. Secondly, genes facilitating lung expansion are up-regulated [39] including: surfactant proteins SP-A, SP-B, and SP-C; fatty acid synthase [40 • ] and ABCA3 [41], an ATP-binding cassette transporter (probably of phospholipids) mutated in fatal surfactant deficiency in human neonates. Thirdly, antioxidant enzyme systems that protect lung when aerated are induced including catalase, glutathione peroxidase, and two superoxide dismutases [40 • ].…”