Effect of Two Models of Intrauterine Growth Restriction on Alveolarization in Rat Lungs: Morphometric and Gene Expression Analysis

Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and –R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization.

[1]  A. Malamitsi‐Puchner,et al.  Small for gestational age birth weight: impact on lung structure and function. , 2013, Paediatric respiratory reviews.

[2]  S. Mayeur,et al.  Maternal hypertension induced by NO blockade does not program adult metabolic diseases in growth-restricted rat fetuses. , 2013, Metabolism: Clinical and Experimental.

[3]  H. D. Liggitt,et al.  Choriodecidual Infection Downregulates Angiogenesis and Morphogenesis Pathways in Fetal Lungs from Macaca Nemestrina , 2012, PloS one.

[4]  C. Delacourt,et al.  Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development. , 2011, Physiological genomics.

[5]  H. Schneider,et al.  Inhibition of TGF-β Signaling and Decreased Apoptosis in IUGR-Associated Lung Disease in Rats , 2011, PloS one.

[6]  G. Osol,et al.  Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. , 2011, American journal of physiology. Heart and circulatory physiology.

[7]  L. Thaete,et al.  Pathophysiology of Chronic Nitric Oxide Synthase Inhibition-Induced Fetal Growth Restriction in the Rat , 2011, Hypertension in pregnancy.

[8]  W. Künzel,et al.  Impact of fetal growth restriction on mortality and morbidity in a very preterm birth cohort. , 2010, The Journal of pediatrics.

[9]  W. Thomas,et al.  Chorioamnionitis: Important Risk Factor or Innocent Bystander for Neonatal Outcome? , 2010, Neonatology.

[10]  B. Thébaud,et al.  Adrenomedullin promotes lung angiogenesis, alveolar development, and repair. , 2010, American journal of respiratory cell and molecular biology.

[11]  H. Halliday.  Neonatal management and long-term sequelae. , 2009, Best practice & research. Clinical obstetrics & gynaecology.

[12]  Ş..  Programming of hepatic and peripheral tissue insulin sensitivity by maternal protein restriction , 2009 .

[13]  C. Delacourt,et al.  Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats , 2008, PloS one.

[14]  A. Rosenberg.  The IUGR newborn. , 2008, Seminars in perinatology.

[15]  F. Canon,et al.  Effect of a low-protein diet during pregnancy on skeletal muscle mechanical properties of offspring rats. , 2008, Nutrition.

[16]  S. Ozanne,et al.  Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[17]  Guoyao Wu,et al.  Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. , 2008, The Journal of nutrition.

[18]  U. Simeoni,et al.  Kidney gene expression analysis in a rat model of intrauterine growth restriction reveals massive alterations of coagulation genes. , 2007, Endocrinology.

[19]  L. Doyle,et al.  Respiratory function at age 8–9 years in extremely low birthweight/very preterm children born in Victoria in 1991–1992 , 2006, Pediatric pulmonology.

[20]  S. Archer,et al.  Vascular Endothelial Growth Factor Gene Therapy Increases Survival, Promotes Lung Angiogenesis, and Prevents Alveolar Damage in Hyperoxia-Induced Lung Injury: Evidence That Angiogenesis Participates in Alveolarization , 2005, Circulation.

[21]  A. Denjean,et al.  Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats , 2005, Pediatric Research.

[22]  C. Delacourt,et al.  Control Mechanisms of Lung Alveolar Development and Their Disorders in Bronchopulmonary Dysplasia , 2005, Pediatric Research.

[23]  Jeffrey S. Robinson,et al.  Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. , 2005, Physiological reviews.

[24]  L. Monte,et al.  [Bronchopulmonary dysplasia]. , 2005, Jornal de pediatria.

[25]  M. C. Rueda,et al.  Prolonged inhibition of nitric oxide synthesis in pregnant rats: effects on blood pressure, fetal growth and litter size , 2005, Archives of Gynecology and Obstetrics.

[26]  A. Greenough,et al.  Effect of in utero growth retardation on lung function at follow-up of prematurely born infants , 2004, European Respiratory Journal.

[27]  R. Harding,et al.  Fetal Growth Restriction Has Long-Term Effects on Postnatal Lung Structure in Sheep , 2004, Pediatric Research.

[28]  J. G. Douglas,et al.  Relationship between birth weight and adult lung function: controlling for maternal factors , 2003, Thorax.

[29]  C. Giulio,et al.  The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia , 2003, Pediatric Research.

[30]  C. Delacourt,et al.  Pre- and Postnatal Lung Development, Maturation, and Plasticity LPS-induced lung injury in neonatal rats: changes in gelatinase activities and consequences on lung growth , 2002 .

[31]  R. Harding,et al.  Effects of fetal growth restriction on lung development before and after birth: A morphometric analysis , 2001, Pediatric pulmonology.

[32]  C. Deng,et al.  FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. , 1998, Development.

[33]  S. Ozanne,et al.  Early protein restriction and obesity independently induce hypertension in 1-year-old rats. , 1997, Clinical science.

[34]  C. Yallampalli,et al.  Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. , 1993, American journal of obstetrics and gynecology.

[35]  K. Godfrey,et al.  Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. , 1991, BMJ.

[36]  E. Weibel,et al.  The postnatal growth of the rat lung II. Autoradiography , 1974, The Anatomical record.

[37]  E. Weibel,et al.  The postnatal growth of the rat lung. I. Morphometry , 1974, The Anatomical record.

[38]  Weibel Er.  Morphometric studies on the growth of gas exchange capacity of the rat lung , 1966 .

[39]  E. Weibel.  [Morphometric studies on the growth of gas exchange capacity of the rat lung]. , 1966, Helvetica physiologica et pharmacologica acta.

[40]  J. Emery,et al.  The Number of Alveoli in the Terminal Respiratory Unit of Man During Late Intrauterine Life and Childhood , 1960, Archives of disease in childhood.