Temporary tracheal occlusion in fetal sheep with lung hypoplasia does not improve postnatal lung function

2003 ◽  
Vol 94 (3) ◽  
pp. 1054-1062 ◽  
Author(s):  
Marcus G. Davey ◽  
Holly L. Hedrick ◽  
Sarah Bouchard ◽  
Julianne M. Mendoza ◽  
Uwe Schwarz ◽  
...  
Keyword(s):  
Lung Function ◽  
Mrna Expression ◽  
Surfactant Protein ◽  
Lung Compliance ◽  
Lung Hypoplasia ◽  
Alveolar Wall ◽  
Blood Gas ◽  
Fetal Sheep ◽  
Tracheal Occlusion ◽  
Alveolar Epithelial

Prolonged fetal tracheal occlusion (TO) accelerates lung growth but leads to loss of alveolar epithelial type II (AE2) cells. In contrast, temporary TO leads to recovery of AE2 cells and their ability to produce surfactant. The aim of this study was to determine the effects of temporary TO in fetal sheep with lung hypoplasia on postnatal lung function, structure, and surfactant protein mRNA expression. Diaphragmatic hernia (DH) was created in 22 fetal sheep at 65 days of gestation. TO was performed between 110 days of gestation and full term (DH/TO, n = 7) and between 110 and 130 days of gestation (DH/TO+R, n = 6). Sham-operated fetuses ( n = 11) served as controls. Lambs were delivered at ∼139 days of gestation, and blood gas tensions were monitored over a 2-h resuscitation period. Temporary TO increased growth of the hypoplastic lung and restored surfactant protein mRNA expression and AE2 cell density but did not improve respiratory function above that of animals that underwent prolonged TO; DH/TO and DH/TO+R lambs were hypoxic and hypercapnic compared with Sham animals. Lung compliance remained low in DH/TO+R lambs, most likely as a consequence of the persistent increase in alveolar wall thickness in these animals.

Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung

2002 ◽  
Vol 282 (3) ◽  
pp. L411-L420 ◽  
Author(s):  
Karen E. Willet ◽  
Boris W. Kramer ◽  
Suhas G. Kallapur ◽  
Machiko Ikegami ◽  
John P. Newnham ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lung Function ◽  
Lung Inflammation ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Lung Compliance ◽  
Fetal Membranes ◽  
Lung Maturation ◽  
Fetal Sheep ◽  
Fetal Lung Maturation

Antenatal inflammation may be an important triggering event in the pathogenesis of bronchopulmonary dysplasia but may also accelerate fetal lung maturation. We examined the effects of intra-amniotic (IA) interleukin (IL)-1α and IL-1β on maturation of the fetal sheep lung. These cytokine effects were compared with IA endotoxin, a potent proinflammatory stimulus that accelerated lung maturation. Date-bred ewes received 15 or 150 μg recombinant ovine IL-1α or IL-1β or 10 mg Escherichia coli endotoxin by IA injection at 118 days gestation (term = 150 days), and fetuses were delivered at 125 days. IL-1α and IL-1β improved lung function and increased alveolar saturated phosphatidylcholine (Sat PC) and surfactant protein mRNA expression at the higher dose. The maturation response to IL-1α was greater than that to IL-1β, which was similar to endotoxin response. Inflammation was also more pronounced after IL-1α treatment. Only endotoxin animals had residual inflammation of the fetal membranes at 7 days. Lung compliance, lung volume, and alveolar Sat PC were positively correlated with residual alveolar wash leukocyte numbers 7 days after IL-1 treatment, suggesting a link between lung inflammation and maturation.

scholarly journals Effects of budesonide and surfactant in preterm fetal sheep

2018 ◽  
Vol 315 (2) ◽  
pp. L193-L201 ◽  
Author(s):  
T. Brett Kothe ◽  
Emily Royse ◽  
Matthew W. Kemp ◽  
Augusto Schmidt ◽  
Fabrizio Salomone ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Function ◽  
Inflammatory Responses ◽  
Fetal Surgery ◽  
Surfactant Protein ◽  
Lung Compliance ◽  
Fetal Head ◽  
Fetal Sheep ◽  
Monocyte Chemoattractant Protein 1 ◽  
Lung Liquid

Mechanical ventilation causes lung injury and systemic inflammatory responses in preterm sheep and is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Budesonide added to surfactant decreased BPD by 20% in infants. We wanted to determine the effects of budesonide and surfactant on injury from high tidal volume (VT) ventilation in preterm lambs. Ewes at 125 ± 1 days gestational age had fetal surgery to expose fetal head and chest with placental circulation intact. Lambs were randomized to 1) mechanical ventilation with escalating VT to target 15 ml/kg by 15 min or 2) continuous positive airway pressure (CPAP) of 5 cmH2O. After the 15-min intervention, lambs were given surfactant 100 mg/kg with saline, budesonide 0.25 mg/kg, or budesonide 1 mg/kg. The fetuses were returned to the uterus for 24 h and then delivered and ventilated for 30 min to assess lung function. Budesonide levels were low in lung and plasma. CPAP groups had improved oxygenation, ventilation, and decreased injury markers compared with fetal VT lambs. Budesonide improved ventilation in CPAP lambs. Budesonide decreased lung weights and lung liquid and increased lung compliance and surfactant protein mRNA. Budesonide decreased proinflammatory and acute-phase responses in lung. Airway thickness increased in animals not receiving budesonide. Systemically, budesonide decreased monocyte chemoattractant protein-1 mRNA and preserved glycogen in liver. Results with 0.25 and 1 mg/kg budesonide were similar. We concluded that budesonide with surfactant matured the preterm lung and decreased the liver responses but did not improve lung function after high VT injury in fetal sheep.

Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus

2010 ◽  
Vol 298 (4) ◽  
pp. L575-L583 ◽  
Author(s):  
Sandra Orgeig ◽  
Tamara A. Crittenden ◽  
Ceilidh Marchant ◽  
I. Caroline McMillen ◽  
Janna L. Morrison
Keyword(s):  
Mrna Expression ◽  
Plasma Cortisol ◽  
Surfactant Protein ◽  
Cortisol Concentration ◽  
Plasma Catecholamine ◽  
Fetal Sheep ◽  
C Protein ◽  
Intrauterine Growth ◽  
Plasma Cortisol Concentration ◽  
The Impact

Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 ± 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight <2 SD from the mean of control fetuses and a mean gestational PaO2<17 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational PaO2was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

2015 ◽  
Vol 309 (1) ◽  
pp. L84-L97 ◽  
Author(s):  
Sandra Orgeig ◽  
Erin V. McGillick ◽  
Kimberley J. Botting ◽  
Song Zhang ◽  
I. Caroline McMillen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Acute Hypoxia ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Prolyl Hydroxylase ◽  
Fetal Sheep ◽  
Chronic Hypoxemia ◽  
Hypoxia Signaling

Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130–135 ( n = 19) and 139–145 ( n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain ( PHD) 2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α ( HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.

scholarly journals Liraglutide Enhances the Activity of the ACE-2/Ang(1–7)/Mas Receptor Pathway in Lungs of Male Pups from Food-Restricted Mothers and Prevents the Reduction of SP-A

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
J. Fandiño ◽  
A. A. Vaz ◽  
L. Toba ◽  
M. Romaní-Pérez ◽  
L. González-Matías ◽  
...  
Keyword(s):  
Lung Function ◽  
Mrna Expression ◽  
Food Restriction ◽  
Early Stage ◽  
Surfactant Protein ◽  
In Utero ◽  
Respiratory Morbidity ◽  
Alveolar Type ◽  
Lung Maturation ◽  
Positive Effects

In utero growth restriction and being born small for gestational age are risk factors for respiratory morbidity. IUGR (in utero growth retardation) is associated to overall reduction in lung weight, surfactant content and activity, impaired maturation of the alveolar type II cells, and decreased alveolar formation. The renin-angiotensin system (RAS) may be a key target underlying pathophysiological lung alterations. GLP-1 and agonists of its receptor modulate the expression levels of different components of RAS and also are very important for lung maturation and the production of surfactant proteins. The aim of this study was to elucidate the effects of IUGR induced by perinatal food restriction of the mother in the lung function of pups at early stages of life (PD21) and to determine if liraglutide had any effect during gestational period. Sprague-Dawley pregnant rats were randomly assigned to 50% food restriction (MPFR) or ad libitum control (CT) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant MPFR and CT rats were treated with liraglutide or vehicle. At postnatal day 21 and before weaning, 20 CT and 20 FR male pups were sacrificed and lungs were analyzed by RT-PCR. Liraglutide restored surfactant protein A (SP-A) mRNA expression in pup lungs from food-restricted mothers. Surfactant protein B (SP-B) mRNA expression is not affected by neither IUGR nor liraglutide treatment. Moreover, liraglutide modulated different elements of RAS, increasing angiotensin-converting enzyme 2 (ACE2) and MasR mRNA expression only in pups from food-restricted mothers (MPFR), despite food restriction had not any direct effect at this early stage. Liraglutide also increased endothelial nitric oxide synthase (eNOS) expression in MPFR lungs, reflecting the activation of MasR by angiotensin 1–7. In conclusion, liraglutide prevented the alteration in lung function induced by IUGR and promoted the positive effects of ACE2-Ang(1–7)-MasR in restoring lung function.

Effects of mechanical factors on growth and maturation of the lung in fetal sheep

1997 ◽  
Vol 272 (1) ◽  
pp. L95-L105 ◽  
Author(s):  
P. Joe ◽  
L. D. Wallen ◽  
C. J. Chapin ◽  
C. H. Lee ◽  
L. Allen ◽  
...  
Keyword(s):  
Cervical Spinal Cord ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Lung Hypoplasia ◽  
Alveolar Type ◽  
Sham Operation ◽  
Mechanical Forces ◽  
Lung Growth ◽  
Fetal Sheep ◽  
Igf I

Previous fetal studies indicated that endocrine factors control surfactant maturation, whereas mechanical forces affect lung growth, but not surfactant. We altered mechanical forces in fetal sheep lungs at 100-108 days gestation by tracheal ligation (TL, n = 15, 7 successful studies) to accelerate lung growth, transection of cervical spinal cord (TCSC, n = 17, 6 successful studies) to produce lung hypoplasia, or sham operation (n = 11, 6 successful studies). The reasons for the high mortality rates are not known. At delivery (130-142 days), groups were similar in gestational age, weight, and cortisol. Effects on lung growth were similar to, but effects on surfactant differed from, previous reports. TL increased lung growth but decreased saturated phosphatidylcholine (SatPC) and surfactant protein (SP)A and apparently decreased SP-B and relative numbers of alveolar type II cells (based on immunohistochemical studies of 1 animal in each group); TCSC had opposite effects. In contrast to a previous study (J. A. Kitterman, G. C. Liggins, G. A. Campos, J. A. Clements, C. S. Forster, C. H. Lee, and R. K. Creasy, J. Appl. Physiol, 51: 384-390, 1981), SatPC did not correlate with cortisol. We conclude that altering mechanical forces in fetal lung affects not only lung growth but also surfactant maturation and possibly alveolar epithelial differentiation and disturbs the normal correlation between cortisol and surfactant. Associated changes in insulin-like growth factor I (IGF-I; increased by TL, P = 0.003) suggest a possible role for IGF-I in these effects.

Amplification of steroid-mediated SP-B expression by physiological levels of caffeine

2014 ◽  
Vol 306 (1) ◽  
pp. L101-L109 ◽  
Author(s):  
Markus Fehrholz ◽  
Matthias Hütten ◽  
Boris W. Kramer ◽  
Christian P. Speer ◽  
Steffen Kunzmann
Keyword(s):  
Lung Function ◽  
Mrna Expression ◽  
Clinical Importance ◽  
Surfactant Protein ◽  
Arterial Oxygen ◽  
Short Term ◽  
Short Term Treatment ◽  
Pepsinogen C

Factors positively influencing surfactant homeostasis in general and surfactant protein B (SP-B) expression in particular are considered of clinical importance regarding an improvement of lung function in preterm infants. The objective of this study was to identify effects of physiological levels of caffeine on glucocorticoid-mediated SP-B expression in vitro and in vivo. Levels of SP-B and pepsinogen C were quantified by quantitative real-time RT-PCR or immunoblotting in NCI-H441 cells daily exposed to caffeine and/or dexamethasone (DEX). In vivo, SP-B expression was analyzed in bronchoalveolar lavage (BAL) of preterm sheep exposed to antenatal DEX and/or postnatal caffeine. If DEX and caffeine were continuously present, SP-B mRNA and protein levels were increased for up to 6 days after induction ( P < 0.05). Additionally, caffeine enhanced SP-B mRNA expression in DEX-pretreated cells ( P < 0.05). Moreover, caffeine amplified DEX-induced pepsinogen C mRNA expression ( P < 0.05). After short-term treatment with caffeine in vivo, only slightly higher SP-B levels could be detected in BAL of preterm sheep following antenatal DEX, combined with an increase of arterial oxygen partial pressure ( P < 0.01). Our data demonstrated that the continuous presence of caffeine in vitro is able to amplify DEX-mediated SP-B expression. In contrast, short-term improvement of lung function in vivo is likely to be independent of altered SP-B transcription and translation. An impact of caffeine on release of surfactant reservoirs from lamellar bodies could, however, quickly affect SP-B content in BAL, which has to be further investigated. Our findings indicate that caffeine is able to amplify main effects of glucocorticoids that result from changes in surfactant production, maturation, and release.

Intra-amniotic endotoxin increases pulmonary surfactant proteins and induces SP-B processing in fetal sheep

2001 ◽  
Vol 280 (2) ◽  
pp. L279-L285 ◽  
Author(s):  
Cindy J. Bachurski ◽  
Gary F. Ross ◽  
Machiko Ikegami ◽  
Boris W. Kramer ◽  
Alan H. Jobe
Keyword(s):  
Bronchoalveolar Lavage ◽  
Gestational Age ◽  
Bronchoalveolar Lavage Fluid ◽  
Fetal Lung ◽  
Lavage Fluid ◽  
Surfactant Protein ◽  
Lung Compliance ◽  
Lung Maturation ◽  
Fetal Sheep ◽  
Pulmonary Surfactant Proteins

Intra-amniotic (IA) endotoxin induces lung maturation within 6 days in fetal sheep of 125 days gestational age. To determine the early fetal lung response to IA endotoxin, the timing and characteristics of changes in surfactant components were evaluated. Fetal sheep were exposed to 20 mg of Escherichia coli 055:B5 endotoxin by IA injection from 1 to 15 days before preterm delivery at 125 days gestational age. Surfactant protein (SP) A, SP-B, and SP-C mRNAs were maximally induced at 2 days. SP-D mRNA was increased fourfold at 1 day and remained at peak levels for up to 7 days. Bronchoalveolar lavage fluid from control animals contained very little SP-B protein, 75% of which was a partially processed intermediate. The alveolar pool of SP-B was significantly increased between 4 and 7 days in conjunction with conversion to the fully processed active airway peptide. All SPs were significantly elevated in the bronchoalveolar lavage fluid by 7 days. IA endotoxin caused rapid and sustained increases in SP mRNAs that preceded the increase in alveolar saturated phosphatidylcholine processing of SP-B and improved lung compliance in prematurely delivered lambs.

Sign in / Sign up

Export Citation Format

Share Document