KGF regulates pulmonary epithelial proliferation and surfactant protein gene expression in adult rat lung

Yano, Toshiyuki; Mason, Robert J.; Pan, Tianli; Deterding, Robin R.; Nielsen, Larry D.; Shannon, John M.

doi:10.1152/ajplung.2000.279.6.l1146

Cited by 123 publications

(106 citation statements)

References 40 publications

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“…Total cellular RNA was isolated by ultracentrifugation for 18 h at 150,000 g through a 5.7 M CsCl cushion. Total RNA isolated from type II cells was analyzed for surfactant protein mRNA expression with a ribonuclease protection assay (RPA) that allowed simultaneous measurement of mRNAs for SP-A, -B, -C, and -D as described previously (46,54). The primers used to generate the riboprobes and their sizes have been reported (54).…”

Section: Methodsmentioning

confidence: 99%

“…Keratinocyte growth factor (KGF), fibroblast growth factor (FGF)-7, and acidic FGF (FGF-1) increase expression of surfactant proteins A, B, and D (SP-A, SP-B, and SP-D, respectively) (46,48,52). Both SP-A and SP-D are increased in lavage fluid of rats instilled with KGF (54). Corticosteroids are especially stimulatory for the expression of SP-B but may be inhibitory for SP-A and SP-C (2,46).…”

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confidence: 99%

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Maintenance of surfactant protein A and D secretion by rat alveolar type II cells in vitro

Mason

Lewis

Edeen

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Secretion of surfactant proteins A and D (SP-A and SP-D) has been difficult to study in vitro because a culture system for maintaining surfactant secretion has been difficult to establish. We evaluated several growth factors, corticosteroids, rat serum, and a fibroblast feeder layer for the ability to produce and maintain a polarized epithelium of type II cells that secretes SP-A and SP-D into the apical medium. Type II cells were plated on a filter insert coated with an extracellular matrix and were cultured at an air-liquid interface. Keratinocyte growth factor (KGF) stimulated type II cell proliferation and secretion of SP-A and SP-D more than fibroblast growth factor-10 (FGF-10), hepatocyte growth factor (HGF), or heparin-binding epidermal-like growth factor (HB-EGF). Cells cultured in the presence of KGF and rat serum with or without fibroblasts had high surfactant protein mRNA levels and exhibited a high level of SP-A and SP-D secretion. Dexamethasone inhibited type II cell proliferation but increased expression of SP-B. In the presence of KGF, rat serum, and dexamethasone, the mRNAs for the surfactant proteins were maintained at high levels. Secretion of SP-A and SP-D was found to be independent of phospholipid secretion.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Maintenance of surfactant protein A and D secretion by rat alveolar type II cells in vitro

Mason

Lewis

Edeen

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…8). Growth factor signaling is an essential component of the regulatory network controlling proliferation, differentiation and pattern formation of the lung (Cardoso et al, 1997;Yano et al, 2000;Mason et al, 2003;Portnoy et al, 2004). As TGF␤2 signaling is known to inhibit lung maturation and type II cell differentiation (Whitsett et al, 1992;Lebeche et al, 1999), effects of Cebpa deletion may be mediated in part by increased expression of TGF␤2.…”

Section: Research Article C/ebp␣ Is Required For Lung Maturationmentioning

confidence: 99%

C/EBPα is required for lung maturation at birth

et al. 2006

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Epithelial cells lining the peripheral lung synthesize pulmonary surfactant that reduces surface tension at the air-liquid interface. Lack of surfactant lipids and proteins in the lungs causes respiratory distress syndrome, a common cause of morbidity and mortality in preterm infants. We show that C/EBP␣ plays a crucial role in the maturation of the respiratory epithelium in late gestation, being required for the production of surfactant lipids and proteins necessary for lung function. Deletion of the Cebpa gene in respiratory epithelial cells in fetal mice caused respiratory failure at birth. Structural and biochemical maturation of the lung was delayed. Normal synthesis of surfactant lipids and proteins, including SP-A, SP-B, SP-C, SP-D, ABCA3 (a lamellar body associated protein) and FAS (precursor of fatty acid synthesis) were dependent upon expression of the C/EBP␣ in respiratory epithelial cells. Deletion of the Cebpa gene caused increased expression of Tgfb2, a growth factor that inhibits lung epithelial cell proliferation and differentiation. Normal expression of C/EBP␣ required Titf1 and Foxa2, transcription factors that also play an important role in perinatal lung differentiation. C/EBP␣ participates in a transcriptional network that is required for the regulation of genes mediating perinatal lung maturation and surfactant homeostasis that is necessary for adaptation to air breathing at birth. Development 133, 1155Development 133, -1164Development 133, (2006 (Perl et al., 2002). Foxa2 ⌬/⌬ mice in which Foxa2 was selectively deleted from the respiratory epithelium were generated as previously reported (Wan et al., 2004). Lungs were obtained at E18.5 from Titf1-null mice, kindly provided by Dr S. Kimura from the National Institutes of Health (Kimura et al., 1996). KEY WORDS: CCAAT/enhancer-binding protein ␣, Respiratory epithelial cell differentiation, Lung maturation, Pulmonary surfactant, ABCA3, FOXA2, TTF1, Mouse Animal husbandry and doxycycline administrationAnimals were maintained in a pathogen-free environment in accordance with protocols approved by the Institutional Animal Care and Use Committee of the Cincinnati Children's Hospital Research Foundation. All animals were housed in humidity-and temperature-controlled rooms on a 12 hour-12 hour light-dark cycle. Mice were allowed food and water ad libitum. There was no serological evidence of pulmonary pathogens or bacterial infections in sentinel mice maintained within the colony. Gestation was dated by detection of the vaginal plug (as E0.5) and correlated with weight of each pup at the time of sacrifice. Dams bearing control and Cebpa ⌬/⌬ mice were maintained on doxycycline in food (625 mg/kg; Harlan Teklad, Madison, WI) from E0. At E18.5, dams were killed by exsanguination and lungs were dissected for analysis. Blood glucose analysisGlucose concentrations in neonatal blood were measured immediately upon collection using Ascensia Elite Blood Glucose Meter (Model 9662A, Bayer) with Ascensia Elite XL Blood Glucose Test Strips that have a 1.1-3...

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“…We found that SU5402 treatment down-regulated 136 epithelial genes (Table 1). These included genes that have been previously described to be FGF-sensitive, such as Sftpa, Sftpb, and Sftpc (Cardoso et al, 1997;Matsui et al, 1999;Tichelaar et al, 2000;Yano et al, 2000;Clark et al, 2001;Hyatt et al, 2004). Of the 136 genes decreased in SU5402-treated epithelium, there were five transcription factors (Hnf4a, Atoh1, Nkx3-1, Trp63, and Elf5).…”

Section: Su5402 Treatment Decreases Expression Of Fgfresponsive Genesmentioning

confidence: 99%

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

Metzger¹,

Xu²,

Shannon³

2007

Developmental Dynamics

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Fibroblast growth factor (FGF) signaling has been shown to be essential for many aspects of normal lung development. To determine epithelial targets of FGF signaling, we cultured embryonic day (E) 11.5 mouse lungs for 24 hr in the presence or absence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis of treated and control epithelia identified several genes regulated by FGF signaling, including Elf5, a member of the Epithelial-specific Ets family of transcription factors. SU5402 reduced Elf5 expression in mesenchyme-free cultures of E12.5 epithelium, demonstrating that the inhibition was direct. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development. We found that expression of Elf5 was induced by FGF7 and FGF10, ligands that primarily bind FGFR2b. To further define the pathways by which FGFs activate Elf5 expression, we cultured E11.5 lung tips in the presence of compounds to inhibit FGF receptors (SU5402), PI3-Kinase/Akt-mediated signaling (LY294002), and MAP Kinase/Erk-mediated signaling (U0126). We found that SU5402 and LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. LY294002 also reduced Elf5 expression in cultures of purified epithelium. Finally, pAkt was coexpressed with Elf5 in the proximal epithelial airways of E17.5 lungs. These results demonstrate that Elf5 is an FGF-sensitive transcription factor in the lung with a dynamic pattern of expression and that FGF regulation of Elf5 by means of FGFR2b occurs through the PI3-Kinase/Akt pathway.

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KGF regulates pulmonary epithelial proliferation and surfactant protein gene expression in adult rat lung

Cited by 123 publications

References 40 publications

Maintenance of surfactant protein A and D secretion by rat alveolar type II cells in vitro

Maintenance of surfactant protein A and D secretion by rat alveolar type II cells in vitro

C/EBPα is required for lung maturation at birth

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

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