rhKGF stimulates lung surfactant production in neonatal rats in vivo

Surfactant deficiency and bronchopulmonary dysplasia (BPD), major obstacles in preterm infants, are addressed with pre‐ and postnatal glucocorticoids which also evoke harmful catabolic side‐effects. Keratinocyte growth factor (KGF) accelerates surfactant production in fetal type II pneumocytes (PN‐II), protects epithelia from injury and is deficient in lungs developing BPD, highlighting its potential efficacy in neonates. Neonatal rats were treated with recombinant human (rh)KGF, betamethasone, or their combination for 48 hr prior to sacrifice after which body weight, surfactant, and tissue phosphatidylcholines (PC) were investigated at postnatal d3, d7, d15, and d21. Pneumocyte proliferation, surfactant protein (SP) expression and SP‐B/C in lung lavage fluid (LLF) were also determined at d7 and d21 to identify broader surfactant changes occurring at the beginning and end of the initial alveolarization phase. While all treatments increased secreted surfactant PC, BM compromised animal growth whereas rhKGF did not. At d3 rhKGF was more effective in male compared to female rats. Single treatments became less effective towards d21. Neither treatment altered PC composition in LLF. BM inhibited PN‐II proliferation and increased surfactant PCs at the expense of tissue PCs. rhKGF however increased surfactant PCs without decreasing other PC species. Whereas SP‐B/C gene expression was induced by all treatments, the changes in secreted SP‐B/C mirrored those observed for surfactant PC. Our results encourage investigation of the mechanisms by which rhKGF improves surfactant homoeostasis, and detailed examination of its efficacy in neonatal lung injury models with a view to implementing it as a non‐catabolic surfactant‐increasing therapeutic in neonatal intensive care. Pediatr. Pulmonol. 2011; 46:883–895. © 2011 Wiley‐Liss, Inc.

[1]  J. Stockman,et al.  Single-Dose Palifermin Prevents Severe Oral Mucositis During Multicycle Chemotherapy in Patients With Cancer: A Randomized Trial , 2012 .

[2]  J. Frank,et al.  Keratinocyte growth factor enhances barrier function without altering claudin expression in primary alveolar epithelial cells. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[3]  E. Schleicher,et al.  Myristate is selectively incorporated into surfactant and decreases dipalmitoylphosphatidylcholine without functional impairment. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  P. Provost,et al.  Gene expression profile of androgen modulated genes in the murine fetal developing lung , 2010, Reproductive biology and endocrinology : RB&E.

[5]  C. Delacourt,et al.  Pulmonary effects of keratinocyte growth factor in newborn rats exposed to hyperoxia. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[6]  E. Autret-Leca,et al.  Corticothérapie postnatale chez le prématuré: étude des pratiques des centres français de néonatologie en 2006 , 2009 .

[7]  B. Kramer,et al.  Endotoxin Induced Chorioamnionitis Prevents Intestinal Development during Gestation in Fetal Sheep , 2009, PloS one.

[8]  Paul O Nkadi,et al.  An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. , 2009, Molecular genetics and metabolism.

[9]  A. Hamvas,et al.  Pulmonary surfactant kinetics of the newborn infant: novel insights from studies with stable isotopes , 2009, Journal of Perinatology.

[10]  L. Doyle,et al.  Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. , 2009, The Cochrane database of systematic reviews.

[11]  I. Tseu,et al.  Evidence and structural mechanism for late lung alveolarization , 2009 .

[12]  F. Stanzel,et al.  Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis , 2008, European Respiratory Journal.

[13]  J. Hohlfeld,et al.  Elastase-induced lung emphysema in rats is not reduced by hematopoietic growth factors when applied preventionally , 2008, Virchows Archiv.

[14]  C. Poets,et al.  Developmental changes in rat surfactant lipidomics in the context of species variability , 2007, Pediatric pulmonology.

[15]  S. Mustafa,et al.  Mechanical Ventilation Down-Regulates Surfactant Protein A and Keratinocyte Growth Factor Expression in Premature Rabbits , 2007, Pediatric Research.

[16]  C. Poets,et al.  Differential effect of surfactant and its saturated phosphatidylcholines on human blood macrophages Published, JLR Papers in Press, November 10, 2006. , 2007, Journal of Lipid Research.

[17]  C. Dammann,et al.  ErbB receptor regulation by dexamethasone in mouse type II epithelial cells , 2006, European Respiratory Journal.

[18]  C. Poets,et al.  Molecular and functional changes of pulmonary surfactant in response to hyperoxia , 2006, Pediatric pulmonology.

[19]  Xuefei Shen,et al.  Role of keratinocyte growth factor in the pathogenesis of autosomal dominant polycystic kidney disease. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[20]  W. Bernhard,et al.  Dipalmitoylphosphatidylcholine is not the major surfactant phospholipid species in all mammals. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[21]  A. Tanswell,et al.  Surfactant palmitoylmyristoylphosphatidylcholine is a marker for alveolar size during disease. , 2005, American journal of respiratory and critical care medicine.

[22]  H. Raff,et al.  Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids. , 2005, Journal of applied physiology.

[23]  J. Wright.  Immunoregulatory functions of surfactant proteins , 2005, Nature Reviews Immunology.

[24]  T. Nagayasu,et al.  Expression of keratinocyte growth factor/fibroblast growth factor‐7 and its receptor in human lung cancer: correlation with tumour proliferative activity and patient prognosis , 2004, The Journal of pathology.

[25]  L. D. Nielsen,et al.  Transforming growth factor-beta antagonizes alveolar type II cell proliferation induced by keratinocyte growth factor. , 2004, American journal of respiratory cell and molecular biology.

[26]  C. Poets,et al.  Surfactant in newborn compared with adolescent pigs: adaptation to neonatal respiration. , 2004, American journal of respiratory cell and molecular biology.

[27]  N. Krug,et al.  Keratinocyte growth factor transiently alters pulmonary function in rats. , 2004, Journal of applied physiology.

[28]  D. Grier,et al.  Effects of Glucocorticoids on Fetal and Neonatal Lung Development , 2004, Treatments in respiratory medicine.

[29]  T. Kasahara,et al.  The gene expression of hepatic proteins responsible for DNA repair and cell proliferation in tamoxifen‐induced hepatocarcinogenesis , 2003, Cancer science.

[30]  Simon C Watkins,et al.  Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  N. Krug,et al.  Surfactant homeostasis is maintained in vivo during keratinocyte growth factor-induced rat lung type II cell hyperplasia. , 2003, American journal of respiratory and critical care medicine.

[32]  A. Jobe,et al.  Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[33]  A. Clément,et al.  Dexamethasone Potentiates Keratinocyte Growth Factor-Stimulated SP-A and SP-B Gene Expression in Alveolar Epithelial Cells , 2003, Pediatric Research.

[34]  A. Çeti̇n,et al.  A Placebo-Controlled Comparison of Effects of Repetitive Doses of Betamethasone and Dexamethasone on Lung Maturation and Lung, Liver, and Body Weights of Mouse Pups , 2003, Pediatric research.

[35]  W. Scherbaum,et al.  Effect of proinflammatory cytokines on gene expression of the diabetes-associated autoantigen IA-2 in INS-1 cells. , 2002, Endocrinology.

[36]  C. Delacourt,et al.  High concentrations of keratinocyte growth factor in airways of premature infants predicted absence of bronchopulmonary dysplasia. , 2002, American journal of respiratory and critical care medicine.

[37]  A. Cummins,et al.  The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer , 2002, Cancer Chemotherapy and Pharmacology.

[38]  C. Poets,et al.  Phosphatidylcholine molecular species in lung surfactant: composition in relation to respiratory rate and lung development. , 2001, American journal of respiratory cell and molecular biology.

[39]  J. Westcott,et al.  Rat alveolar type II cells inhibit lung fibroblast proliferation in vitro. , 2001, American journal of respiratory cell and molecular biology.

[40]  M. Welsh,et al.  KGF alters gene expression in human airway epithelia: potential regulation of the inflammatory response. , 2001, Physiological genomics.

[41]  C. Pinteur,et al.  Role of keratinocyte growth factor in the control of surfactant synthesis by fetal lung mesenchyme. , 2001, Endocrinology.

[42]  L. D. Nielsen,et al.  KGF regulates pulmonary epithelial proliferation and surfactant protein gene expression in adult rat lung. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[43]  E. Ingenito,et al.  Pivotal role of anionic phospholipids in determining dynamic behavior of lung surfactant. , 2000, American journal of respiratory and critical care medicine.

[44]  A. Jobe,et al.  Lung development and function in preterm infants in the surfactant treatment era. , 2000, Annual review of physiology.

[45]  T. Ziegler,et al.  Keratinocyte growth factor enhances early gut adaptation in a rat model of short bowel syndrome. , 2000, Veterinary surgery : VS.

[46]  M. Müller,et al.  Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cells in vivo is resolved by differentiation into type I cells and by apoptosis. , 1999, The European respiratory journal.

[47]  H. Shuman,et al.  Hormonal regulation and cellular localization of fatty acid synthase in human fetal lung. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[48]  A. C. Looman,et al.  Fatty acid translocase/CD36 mediates the uptake of palmitate by type II pneumocytes. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[49]  A. Jobe,et al.  Surfactant protein metabolism in vivo. , 1998, Biochimica et biophysica acta.

[50]  D. Kamp,et al.  Keratinocyte growth factor promotes alveolar epithelial cell DNA repair after H2O2 exposure. , 1998, The American journal of physiology.

[51]  D. Lacey,et al.  Keratinocyte growth factor protects murine hepatocytes from tumor necrosis factor–induced apoptosis in vivo and in vitro , 1998, Hepatology.

[52]  C. Poets,et al.  Conductive airway surfactant: surface-tension function, biochemical composition, and possible alveolar origin. , 1997, American journal of respiratory cell and molecular biology.

[53]  A. Jobe,et al.  Keratinocyte growth factor increases surfactant pool sizes in premature rabbits. , 1997, American journal of respiratory and critical care medicine.

[54]  J. Whitsett,et al.  Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[55]  J. Rubin,et al.  Keratinocyte growth factor increases mRNAs for SP-A and SP-B in adult rat alveolar type II cells in culture. , 1995, The American journal of physiology.

[56]  R. Whitehead,et al.  Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. , 1994, The Journal of clinical investigation.

[57]  A. Postle,et al.  Surfactant phosphatidylcholine composition during dexamethasone treatment in chronic lung disease , 1994, Archives of disease in childhood. Fetal and neonatal edition.

[58]  A. Jobe,et al.  Changes in Alveolar Surface Area, Surfactant Protein A, and Saturated Phosphatidylcholine with Postnatal Rat Lung Growth , 1994, Pediatric Research.

[59]  A. Jobe,et al.  Surfactant function in respiratory distress syndrome. , 1983, The Journal of pediatrics.

[60]  F. Adams,et al.  Lung phospholipids of human fetuses and infants with and without hyaline membrane disease. , 1970, The Journal of pediatrics.

[61]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[62]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.