Abstract
Surfactant-associated proteins (SP-A, SP-B, and SP-C) are critical for the endogenous function of surfactant. Keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF) are key regulators of lung development. The objective of this study was to evaluate the effects of early mechanical ventilation on the expression of these important regulatory proteins in a preterm rabbit model. Premature fetuses were delivered at 29 d of gestation and randomized to necropsy at birth, i.e. no ventilation (NV), spontaneous breathing (SB), or mechanical ventilation (MV) for 16 h. MV animals were further randomized to treatment with dexamethasone (dex). Our findings showed that SB rabbits increased their expression of SP-A mRNA and protein after birth compared with NV controls. MV significantly attenuated this response in the absence of dex. Exposure to dex elevated SP-B mRNA expression in both SB and MV rabbits. KGF protein levels were markedly increased in SB animals compared with MV counterparts. VEGF levels were similar in SB and MV animals, but were significantly increased compared with NV controls. These data suggest that MV alters surfactant-associated protein and growth factor expression, which may contribute to injury in the developing lung.
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Abbreviations
- dex:
-
dexamethasone
- KGF:
-
keratinocyte growth factor
- MV:
-
mechanical ventilation
- NV:
-
nonventilated
- pro-SP-B (-C):
-
prosurfactant protein B (C)
- SB:
-
spontaneous breathing
- SP-A (-B) (-C):
-
surfactant protein A (B) (C)
- VILI:
-
ventilator-induced lung injury
References
Notter RH 2000 Functional composition and component biophysics of endogenous lung surfactant. In: Lenfant C (ed) Lung surfactants: basic science and clinical applications. Marcel Dekker, New York, pp 185–188
Wright JR, Borron P, Brinker KG, Folz RJ 2001 Surfactant protein A: regulation of innate and adaptive immune responses in lung inflammation. Am J Respir Cell Mol Biol 24: 513–517
McCormack FX, Whitsett JA 2002 The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J Clin Invest 109: 707–712
Ware LB, Matthay MA 2002 Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 282: L924–L940
Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA 1989 Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A 86: 802–806
Welsh DA, Summer WR, Dobard EP, Nelson S, Mason CM 2000 Keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model. Am J Respir Crit Care Med 162: 1081–1086
Oswari J, Matthay MA, Margulies SS 2001 Keratinocyte growth factor reduces alveolar epithelial susceptibility to in vitro mechanical deformation. Am J Physiol Lung Cell Mol Physiol 281: L1068–L1077
Sugahara K, Rubin JS, Mason RJ, Aronsen EL, Shannon JM 1995 Keratinocyte growth factor increases mRNAs for SP-A and SP-B in adult rat alveolar type II cells in culture. Am J Physiol 269: L344–L350
Guery BP, Mason CM, Dobard EP, Beaucaire G, Summer WR, Nelsen S 1997 Keratinocyte growth factor increases transalveolar sodium resorption in normals and injured rat lungs. Am J Respir Crit Care Med 155: 1777–1784
Bhatt AJ, Amin SB, Chess PR, Watkins RH, Maniscalco WM 2000 Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung. Pediatr Res 47: 606–613
Zeng X, Wert SE, Federici R, Peters KG, Whitsett JA 1998 VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo. Dev Dyn 211: 215–227
Brown KR, England KM, Goss KI, Snyder JM, Acarregui MJ 2001 VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281: L1001–L1010
Boussat S, Eddahibi S, Coste A, Fataccioli V, Gouge M, Housset B, Adnot S, Maitre B 2000 Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 279: L371–L378
Mura M, dos Santos C, Stewart D, Liu M 2004 Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol 97: 1605–1617
Maniscalco WM, Watkins RH, Pryhuber GS, Bhatt A, Shea C, Huyck H 2002 Angiogenic factors and alveolar vasculature: development and alterations by injury in very premature baboons. Am J Physiol Lung Cell Mol Physiol 282: L811–L823
Dobbs LG, Gutierrez JA 2001 Mechanical forces modulate alveolar epithelial phenotype expression. Comp Biochem Physiol A Mol Integr Physiol 129: 261–266
Liu M, Post M 2000 Invited review: mechanochemical signal transduction in the fetal lung. J Appl Physiol 89: 2078–2084
Dos Santos CC, Slutsky AS 2000 Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol 89: 1645–1655
Tremblay LN, Slutsky AS 1998 Ventilator-induced lung injury: from barotrauma to biotrauma. Proc Assoc Am Physicians 110: 482–488
Wirtz HR, Dobbs LG 1990 Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 250: 1266–1269
Sanchez-Esteban J, Tsai SW, Sang J, Qin J, Torday JS, Rubin LP 1998 Effects of mechanical forces on lung-specific gene expression. Am J Med Sci 316: 200–204
Schellhase DE, Shannon JM 1991 Effects of dexamethasone on expression of SP-A, SP-B and SP-C in the fetal rat lung. Am J Respir Cell Mol Biol 4: 304–312
Ballard PL, Ning Y, Polk D, Ikegami M, Jobe AH 1997 Glucocorticoid regulation of surfactant components in immature lambs. Am J Physiol 273: L1048–L1057
Wang JY, Yeh T, Lin Y, Miyamura K, Holmskov K, Reid KB 1996 Measurement of pulmonary status and surfactant protein levels during dexamethasone treatment of neonatal respiratory distress syndrome. Thorax 51: 907–913
Seidner S, Rider E, Jobe A, Yamada T, Ikegami M 1992 Effects of antenatal thyrotropin-releasing hormone, antenatal corticosteroids, and postnatal ventilation on surfactant mobilization in premature rabbits. Am J Obstet Gynecol 166: 1551–1559
Lewis JF, Jobe AH 1993 Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 147: 218–233
King RJ, Coalson JJ, deLemos RA, Gerstmann SR, Seidner SR 1995 Surfactant protein A deficiency in a primate model of bronchopulmonary dysplasia. Am J Respir Crit Care Med 151: 1989–1997
Hallman M, Merritt TA, Akino T, Bry K 1991 Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Am Rev Respir Dis 144: 1376–1384
Bohlin K, Bouhafs R, Jarstrand C, Cursedt T, Blennow M, Robertson B 2005 Spontaneous breathing or mechanical ventilation alters compliance and tissue association of exogenous surfactant in preterm newborn rabbits. Pediatr Res 57: 624–630
Woods E, Ohashi T, Polk D, Ikegami M, Ueda T, Jobe AH 1995 Surfactant treatment and ventilation effects on SP-A, SP-B, and SP-C mRNA levels in preterm lamb lungs. Am J Physiol 269: L209–L214
Mendelson CR, Alcorn JL, Gao E 1993 The pulmonary surfactant protein genes and their regulation in fetal lung. Semin Perinatol 17: 223–232
Beers MF, Shuman H, Liley HG, Floros J, Gonxales LW, Yue N, Ballard PL 1995 Surfactant protein B in human fetal lung: developmental and glucocorticoid regulation. Pediatr Res 38: 668–675
Stern JB, Fierobe L, Paugam C, Rolland C, Dehoux M, Petiet A, Dombret MC, Mantz J, Aubier M, Crestani B 2000 Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients. Crit Care Med 28: 2326–2333
Danan C, Franco ML, Jarreau PH, Dassieu G, Chailley-Heu B, Bourbon J, Delacourt C 2002 High concentrations of keratinocyte growth factor in airways of premature infants predicted absence of bronchopulmonary dysplasia. Am J Respir Crit Care Med 165: 1384–1387
Mason RJ, Lewis MC, Edeen KE, McCormick-Shannon K, Nielsen LD, Shannon JM 2002 Maintenance of surfactant protein A and D secretion by rat alveolar type II cells in vitro. Am J Physiol Lung Cell Mol Physiol 282: L249–L258
Chelly N, Henrion A, Pinteur C, Chailley-Heu B, Bourbon JR 2001 Role of keratinocyte growth factor in the control of surfactant synthesis by fetal lung mesenchyme. Endocrinology 142: 1814–1819
Mouhieddine-Gueddiche OB, Pinteur C, Chailley-Heu B, Barlier-Mur AM, Clement A, Bourbon JR 2003 Dexamethasone potentiates keratinocyte growth factor-stimulated SP-A and SP-B gene expression in alveolar epithelial cells. Pediatr Res 53: 231–239
Maniscalco WM, Watkins RH, D'Angio CT, Ryan RM 1997 Hyperoxic injury decreases alveolar epithelial cell expression of vascular endothelial growth factor (VEGF) in neonatal rabbit lung. Am J Respir Cell Mol Biol 16: 557–567
Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M 1998 Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol 341: 309–315
Committee on Fetus and Newborn 2002 Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 109: 330–338
Acknowledgements
The authors thank Lori Nielsen for her technical expertise in assisting with the KGF and VEGF ELISAs.
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The opinions expressed in this paper are solely those of the authors and do not represent the views of the United States Air Force, United States Army, Department of Defense, or the United States Government.
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Digeronimo, R., Mustafa, S., Ryan, R. et al. Mechanical Ventilation Down-Regulates Surfactant Protein A and Keratinocyte Growth Factor Expression in Premature Rabbits. Pediatr Res 62, 277–282 (2007). https://doi.org/10.1203/PDR.0b013e3181256aeb
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DOI: https://doi.org/10.1203/PDR.0b013e3181256aeb
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