Pulmonary Surfactant Dysfunction in Congenital Diaphragmatic Hernia: Experimental and Clinical Findings

Valls‐i‐Soler, Adolf; Alfonso, Luisa F.; Arnaiz, Arantzazu; Álvarez, Francisco J.; Tovar, Juan A.

doi:10.1159/000244326

Cited by 15 publications

(9 citation statements)

References 24 publications

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“…Surfactant production by type 2 pneumocytes is a further adaptation that assists in lung inflation at birth and resists airspace collapse. Surfactant deficiency is associated with respiratory distress syndrome in premature newborns and may occur in other disorders such as CDH [34,35]. Estimation of lung maturity has been attempted by assaying surfactant-related metabolites in amniotic fluid [36][37][38].…”

Section: An Overview Of Lung Development Reveals Points Of Clinical Imentioning

confidence: 99%

Exploiting mechanical stimuli to rescue growth of the hypoplastic lung

Jesudason

2007

Pediatr Surg Int

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Impaired lung development afflicts a range of newborns cared for by paediatric surgeons. As a result the speciality has led in the development of surgical models that illustrate the biomechanical regulation of lung growth. Using transgenic mutants, biologists have similarly discovered much about the biochemical regulation of prenatal lung growth. Airway smooth muscle (ASM) and its prenatal contractility airway peristalsis (AP) represent a novel link between these areas: ASM progenitors produce an essential biochemical factor for lung morphogenesis, whilst calcium-driven biomechanical ASM activity appears to regulate the same. In this invited paper, I take the opportunity both to review our recent findings on lung growth and prenatal ASM, and also to discuss mechanisms by which ASM contractility can regulate growth. Finally, I will introduce some novel ideas for exploration: ASM contractility could help to schedule parturition (pulmonary parturition clock) and could even be a generic model for smooth muscle regulation of morphogenesis in similar organs.

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Section: An Overview Of Lung Development Reveals Points Of Clinical Imentioning

confidence: 99%

Exploiting mechanical stimuli to rescue growth of the hypoplastic lung

Jesudason

2007

Pediatr Surg Int

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“…Biochemical lung immaturity in CDH has been demonstrated in human and rat material on the basis of histology [9] , decreased phospholipids [10,11] and decreased SP-B mRNA [12][13][14] . This concept has recently been challenged by quantitative radioactive in situ hybridization measurements of surfactant proteins in lungs of nitrofen-treated rats [15] but this issue remains open.…”

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confidence: 99%

Effects of Nitrofen and Vitamins A, C and E on Maturation of Cultured Human H441 Pneumocytes

et al. 2006

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Background/Aim: Nitrofen (2,4-dichloro-4´-nitrodiphenyl ether), a teratogen with oxidant properties, induces congenital diaphragmatic hernia (CDH) with lung hypoplasia and delayed lung development and maturation in rat embryos. Several phenotypic features of the alveolar epithelium including surfactant proteins A and B synthesis and its regulation by transcription factors are reproduced in cultured human H441 pneumocytes. The aim of the present study was to test whether vitamins A, E and C with anti-oxidant properties were able to recover the expression of such regulators in an in vitro setting. Materials and Methods: Cultured human H441 pneumocytes were treated with nitrofen with or without additional exposure to vitamins A, E and C. Thyroid transcription factor 1 (TTF-1), hepatocyte nuclear factor 3-β (HNF-3β) and hepatocyte nuclear factor 3-β surfactant protein B (SP-B) mRNAs were measured by real-time polymerase chain reaction (RT-PCR). The cells were also immunohistochemically stained for assessment of proliferation (PCNA) and apoptosis (bis-benzimide) status and SP-B and TTF-1 protein expressions. Results were compared by ANOVA with a significant threshold of 5%. Results: Nitrofen severely decreased TTF-1, HNF-3β and SP-B mRNA expression by H441 pneumocytes in culture. Addition of vitamin E normalized the levels of the three transcripts, while vitamin A normalized only those of TTF-1 and SP-B mRNA. Vitamin C was significantly beneficial only for SP-B transcript. Nitrofen decreased proliferation and TTF-1 and SP-B protein expressions with no apparent effect on apoptosis. Additional exposure to vitamins A, C or E rescued near normal values. Conclusions: The changes induced by nitrofen in cultured H441 human pneumocytes are reverted in part by anti-oxidant vitamins by upregulating TTF-1, HNF-3β and SP-B and stimulating proliferation and maturity in nitrofen-treated cells. These effects of anti-oxidant vitamins could be of some interest for developing new transplacental therapeutic strategies aimed at improving lung development and maturation in fetuses with CDH.

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“…However CDH animal models have several limitations. Nitrofen fed pregnant rat mothers produces CDH in about 80% of fetuses (4,8). Interestingly studies applying this method showed structural and biochemical immaturity also in pup lungs that did not develop CDH, raising the concern that Nitrofen exposed rats fetuses may develop lung hypoplasia independently from the occurrence of CDH and therefore by a mechanism different from that occurring in humans (5,7).…”

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Pulmonary Surfactant Disaturated-Phosphatidylcholine (DSPC) Turnover and Pool Size in Newborn Infants with Congenital Diaphragmatic Hernia (CDH)

et al. 2003

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In animal CDH models, surfactant deficiency contributes to the pathophysiology of the condition but information on human disease is very limited. The aim of our study was to investigate surfactant kinetics in CDH newborns. We studied surfactant disaturated-phosphatidylcholine (DSPC) half-life, turnover and apparent pool size by stable isotope methodology in CDH newborns with no ExtraCorporeal Membrane Oxygenation (ECMO) support (n ϭ 13, birth weight (BW) 3.2 Ϯ 2.2 kg, gestational age (GA) 39 Ϯ 0.4 wks, postnatal age 43 Ϯ 11 h) and in 8 term infants with no lung disease (CONTROLS, BW 2.7 Ϯ 0 kg, GA 38 Ϯ 0.8 wks, postnatal age 96 Ϯ 26 h). We administered a trace dose of 13 C-palmitic acid dipalmitoyl-phosphatidylcholine (DPPC) through the endotracheal (ET) tube and we measured DSPC kinetics by gas chromatography-mass spectrometry from DSPC 13 C-enrichment decay curves obtained from sequential tracheal aspirates. DSPC amount from tracheal aspirates (TA-DSPC) was measured by gas chromatography. In CDH infants DSPC half-life was shorter (24 Ϯ 4 and 53 Ϯ 11 h, p ϭ 0.01), turnover faster (0.6 Ϯ 0.1 and 1.5 Ϯ 0.3 d Ϫ1 p ϭ 0.01), apparent pool size smaller (34 Ϯ 6 and 57 Ϯ 7 mg/kg body weight, p ϭ 0.02) and tracheal aspirates DSPC amount lower (2.4 Ϯ 0.4 and 4.6 Ϯ 0.5 mg/mL Epithelial Lining Fluid (ELF), p ϭ 0.007) than in CONTROLS. In conclusion surfactant kinetics is grossly abnormal in mechanically ventilated CDH. Whether alterations of DSPC kinetics in CDH infants are caused by a primary surfactant deficiency or are secondary to oxygen therapy and ventilator support has still to be determined. Clinical and animal studies using air pressure-volume data showed that CDH lungs are significantly less compliant than normal lungs. This finding can be related to lung immaturity, surfactant deficiency, to changes in the amount of collagen and elastic fibers or to lung damage induced by mechanical ventilation (1-3). High-inspired oxygen fraction (Fio 2 ) and positive pressure ventilation may also induce secondary surfactant inactivation and altered surfactant function.It is still unclear whether a primary surfactant deficiency is present in human CDH. CDH animal models showed reduced Received November 18, 2002; accepted February 3, 2003

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Pulmonary Surfactant Dysfunction in Congenital Diaphragmatic Hernia: Experimental and Clinical Findings

Cited by 15 publications

References 24 publications

Exploiting mechanical stimuli to rescue growth of the hypoplastic lung

Exploiting mechanical stimuli to rescue growth of the hypoplastic lung

Effects of Nitrofen and Vitamins A, C and E on Maturation of Cultured Human H441 Pneumocytes

Pulmonary Surfactant Disaturated-Phosphatidylcholine (DSPC) Turnover and Pool Size in Newborn Infants with Congenital Diaphragmatic Hernia (CDH)

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