Abstract
The pathogenesis of congenital cystic adenomatoid malformation (CCAM) is unknown and its natural history is unpredictable. Fatty acid binding protein-7 (FABP-7) has been previously described in brain and breast development, but never before in the lung. We investigate gene expression in CCAM, and hypothesize that CCAM results from an aberration in the signaling pathway during lung development. Under IRB approval, tissue specimens of fetal CCAM, fetal control, postnatal CCAM, and postnatal control were examined and microarray analysis was performed. Candidate differentially expressed genes were selected with log-odds ratio (B) >0 and false discovery rate <0.05. Validation of differential expression was achieved at the RNA and protein levels. FABP-7 was underexpressed in fetal CCAM compared with fetal lung in both the microarray and by RT-PCR. Findings were duplicated by Western Blot analysis and immunohistochemistry. This is the first description of FABP-7 in the human lung. Decreased expression of FABP-7 in fetal CCAM compared with normal fetal lung at both the RNA and protein levels suggests FABP-7 may have a role in pulmonary development and in the pathogenesis of CCAM.
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Abbreviations
- CCAM:
-
congenital cystic adenomatoid malformation
- FABP-7:
-
fatty acid binding protein-7
- CC10:
-
clara cell 10 kilodalton protein
References
MacGillivray TE, Harrison MR, Goldstein RB, Adzick NS 1993 Disappearing fetal lung lesions. J Pediatr Surg 28: 1321–1324
Miller JA, Corteville JE, Langer JC 1996 Congenital cystic adenomatoid malformation in the fetus: natural history and predictors of outcome. J Pediatr Surg 31: 805–808
De Santis M, Masini L, Noia G, Cavaliere AF, Oliva N, Caruso A 2000 Congenital cystic adenomatoid malformation of the lung: antenatal ultrasound findings and fetal-neonatal outcome. Fifteen years of experience. Fetal Diagn Ther 15: 246–250
Stocker JT, Madewell JE, Drake RM 1977 Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 8: 155–171
Riedlinger WF, Vargas SO, Jennings RW, Estroff JA, Barnewolt CE, Lillehei CW, Wilson JM, Colin AA, Reid LM, Kozakewich HP 2006 Bronchial atresia is common to extralobar sequestration, intralobar sequestration, congenital cystic adenomatoid malformation, and lobar emphysema. Pediatr Dev Pathol 9: 361–373
Cangiarella J, Greco MA, Askin F, Perlman E, Goswami S, Jagirdar J 1995 Congenital cystic adenomatoid malformation of the lung: insights into the pathogenesis utilizing quantitative analysis of vascular marker CD34 (QBEND-10) and cell proliferation marker MIB-1. Mod Pathol 8: 913–918
Morotti RA, Cangiarella J, Gutierrez MC, Jagirdar J, Askin F, Singh G, Profitt SA, Wert SE, Whitsett JA, Greco MA 1999 Congenital cystic adenomatoid malformation of the lung (CCAM): evaluation of the cellular components. Hum Pathol 30: 618–625
Liechty KW, Crombleholme TM, Quinn TM, Cass DL, Flake AW, Adzick NS 1999 Elevated platelet-derived growth factor-B in congenital cystic adenomatoid malformations requiring fetal resection. J Pediatr Surg 34: 805–809
Volpe MV, Pham L, Lessin M, Ralston SF, Bhan E, Cutz E, Nielsen HC 2003 Expression of Hoxb-5 during human lung development and in congenital lung malformations. Birth Defects Res A Clin Mol Teratol 67: 550–556
Fromont-Hankard G, Philippe-Chomette P, Delezoide AL, Nessmann C, Aigrain Y, Peuchmaur M 2002 Glial cell-derived neurotrophic factor expression in normal human lung and congenital cystic adenomatoid malformation. Arch Pathol Lab Med 126: 432–436
Bolstad BM, Collin F, Simpson KM, Irizarry RA, Speed TP 2004 Experimental design and low-level analysis of microarray data. Int Rev Neurobiol 60: 25–58
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J 2004 Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP 2003 Summaries of affymetrix genechip probe level data. Nucleic Acids Res 31: e15
Hogan BL, Yingling JM 1998 Epithelial/mesenchymal interactions and branching morphogenesis of the lung. Curr Opin Genet Dev 8: 481–486
Mendelson CR 2000 Role of transcription factors in fetal lung development and surfactant protein gene expression. Annu Rev Physiol 62: 875–915
Chuang PT, McMahon AP 2003 Branching morphogenesis of the lung: new molecular insights into an old problem. Trends Cell Biol 13: 86–91
Cardoso WV, Lu J 2006 Regulation of early lung morphogenesis: questions, facts and controversies. Development 133: 1611–1624
Haunerland NH, Spener F 2004 Fatty acid-binding proteins—insights from genetic manipulations. Prog Lipid Res 43: 328–349
Godbout R, Bisgrove DA, Shkolny D, Day RS 1998 Correlation of B-FABP and GFAP expression in malignant glioma. Oncogene 16: 1955–1962
Wang M, Lui YE, Goldberg ID, Shi YE 2003 Induction of mammary gland differentiation in transgenic mice by the fatty acid-binding protein MRG. J Biol Chem 278: 47319–47325
Paulussen RJ, Geelen MJ, Beynen AC, Veerkamp JH 1989 Immunochemical quantitation of fatty-acid-binding proteins. Tissue and intracellular distribution, postnatal development and influence of physiological conditions on rat heart and liver FABP. Biochim Biophys Acta 1001: 201–209
Guthmann F, Hohoff C, Fechner H, Humbert P, Borchers T, Spener F, Rustow B 1998 Expression of fatty-acid-binding proteins in cells involved in lung-specific lipid metabolism. Eur J Biochem 253: 430–436
Burkhardt R, Von Wichert P, Batenburg JJ, Van Golde LM 1988 Fatty acids stimulate phosphatidylcholine synthesis and CTP: choline-phosphate cytidylyltransferase in type II pneumocytes isolated from adult rat lung. Biochem J 254: 495–500
Balendiran GK, Schnutgen F, Scapin G, Borchers T, Xhong N, Lim K, Godbout R, Spener F, Sacchettini JC 2000 Crystal structure and thermodynamic analysis of human brain fatty acid-binding protein. J Biol Chem 275: 27045–27054
Viscardi RM, Max SR 1993 Unsaturated fatty acid modulation of glucocorticoid receptor binding in L2 cells. Steroids 58: 357–361
Kato J, Takano A, Mitsuhashi N, Koike N, Yoshida K, Hirata S 1987 Modulation of brain progestin and glucocorticoid receptors by unsaturated fatty acid and phospholipid. J Steroid Biochem 27: 641–648
Ballard PL, Ballard RA 1986 Hormones and Lung maturation, Monographs on Endocrinology. Springer-Verlag New York 197–236
Tsao K, Hawgood S, Vu L, Hirose S, Sydorak R, Albanese CT, Farmer DL, Harrison MR, Lee H 2003 Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr Surg 38: 508–510
Peranteau WH, Wilson RD, Liechty KW, Johnson MP, Bebbington MW, Hedrick HL, Flake AW, Adzick NS 2007 Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 22: 365–371
Acknowledgements
The authors thank Dr. Rosaline Godbout for generously providing us with the FABP-7 antibody.
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This study was supported by in part by the UCSF NHLBI Shared Microarray Facility (NIH grant HL072301) and by the General Clinical Research Center at San Francisco General Hospital (RR-00083).
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Wagner, A., Stumbaugh, A., Tigue, Z. et al. Genetic Analysis of Congenital Cystic Adenomatoid Malformation Reveals a Novel Pulmonary Gene: Fatty Acid Binding Protein-7 (Brain Type). Pediatr Res 64, 11–16 (2008). https://doi.org/10.1203/PDR.0b013e318174eff8
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DOI: https://doi.org/10.1203/PDR.0b013e318174eff8
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