Endogenous opioids modulate fetal rabbit lung maturation

To test the hypothesis that endogenous opioids modulate fetal lung development, separate groups of pregnant rabbits received daily injections of saline, morphine (1 mg/kg body wt), or the opioid antagonist naloxone (0.4 and 5.0 mg) for 10 days during their last trimester of pregnancy. The corresponding groups of fetuses were then delivered prematurely on day 28 of gestation (term approximately 31 days) and evaluated with respect to differences in body weight, lung weight, and the ratios of wet to dry lung weight and lung dry weight to body weight, the static inflation and deflation air and saline pressure-volume (P-V) characteristics of the lungs, and lung morphology. Mean values for body weight, lung weight, and the ratios of lung wet to dry weight and lung dry weight to body weight were not significantly different among the saline control (C), morphine (M)-, and naloxone (NLX)-treated fetuses. On the other hand, the fetal air P-V curves varied significantly (P less than 0.001), wherein the M-treated group depicted increased lung distensibility and alveolar stability on lung deflation, whereas the opposite was obtained in the NLX-treated fetuses. Moreover, morphometric analyses demonstrated that the mean alveolar air space-to-tissue ratio in lungs from M-treated fetuses were significantly greater than that observed either in C or in NLX-treated fetuses (P less than 0.05); however, the air space-to-tissue ratio did not significantly vary between the C and NLX-treated animals. These observations provide new evidence that endogenous opioids enhance fetal lung maturation.

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Effect of prenatal isoxsuprine on pulmonary oxygen toxicity in the newborn rat

Journal of Applied Physiology ◽

10.1152/jappl.1980.48.3.505 ◽

1980 ◽

Vol 48 (3) ◽

pp. 505-510 ◽

Cited By ~ 1

Author(s):

L. Frank ◽

J. Summerville ◽

D. Massaro

Keyword(s):

Enzyme Activities ◽

Oxygen Toxicity ◽

Fetal Lung ◽

Antioxidant Enzyme Activities ◽

Newborn Rats ◽

Lung Maturation ◽

Lung Weight ◽

Pregnant Rats ◽

Rat Pups ◽

Hyperoxic Exposure

Isoxsuprine, a beta-sympathomimetic agent used clinically to delay premature parturition and to possibly accelerate fetal lung maturation, was administered to pregnant rats at 48 and 24 h prior to delivery. Newborn rats were placed in 96-98% O2 (or room air) to determine if the prenatal isoxsuprine treatment compromised their tolerance to prolonged hyperoxic exposure. (Exogenous catecholamines are known to exacerbate O2 toxicity in adult animals). Survival of the isoxsuprine-treated pups in O2 (52%) was no different than for control neonates exposed to hyperoxia for 7 days (57%) (P = 0.22). Body weight, lung weight, lung protein, and DNA content of the newborns were also not altered by the prenatal isoxsuprine treatment. Lung antioxidant enzyme activities for superoxide dismutase, catalase, and glutathione peroxidase were the same at birth in the isoxsuprine-treated and control rat pups, and the enzyme activities increased in response to hyperoxic exposure in each group to an equivalent degree. Thus, in utero treatment with isoxsuprine had no apparent adverse effect on newborn rats exposed to a prolonged O2 challenge.

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RADIOLOGIC DEMONSTRATION OF POSTNATAL LIQUID IN THE LUNGS OF NEWBORN LAMBS

PEDIATRICS ◽

10.1542/peds.46.2.252 ◽

1970 ◽

Vol 46 (2) ◽

pp. 252-258

Author(s):

Barry D. Fletcher ◽

Barry F. Sachs ◽

Robert V. Kotas

Keyword(s):

Body Weight ◽

Caesarean Section ◽

Fetal Lung ◽

Lung Compliance ◽

Pleural Effusions ◽

Interstitial Edema ◽

Lung Weight ◽

Lung Aeration ◽

Lung Liquid ◽

Radiologic Evidence

The liquid which occupies the potential air spaces of the fetal lung is, at birth, displaced by air and removed by the pulmonary blood and lymphatic circulations. Delayed resorption of this liquid from the interstitial spaces may be associated with decreased lung compliance and be the cause of the syndrome "transient tachypnea of the newborn." Chest roentgenograms of these infants have shown the presence of alveolar and interstitial edema and pleural effusions which cleared during the first few days of life. We chose to test the possibility that a delay in clearance of lung liquid might occur and be associated with tachypnea and radiologic evidence of pulmonary edema in newborn lambs. Serial chest radiographs were obtained in 18 newborn lambs delivered at term by Caesarean section. The radiographs demonstrated the presence of lung liquid which gradually cleared in an average time of 2 hours following onset of breathing. Lung weight—body weight ratios obtained following sacrifice at various stages of clearing—decreased as pulmonary aeration increased. Microscopic examination of the lungs showed no evidence of inflammatory exudate or squamous debris but distension of perivascular tissues with liquid was demonstrated. An association between increasing lung aeration and decreasing respiratory rates was found.

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DEXAMETHASONE IN THE MANAGEMENT OF KEROSENE PNEUMONIA

PEDIATRICS ◽

10.1542/peds.53.1.86 ◽

1974 ◽

Vol 53 (1) ◽

pp. 86-90

Author(s):

J. Wolfsdorf ◽

Dip. Paed. ◽

H. Kündig

Keyword(s):

Body Weight ◽

Aspiration Pneumonia ◽

Inflammatory Process ◽

Statistical Difference ◽

Dry Weight ◽

Control Group ◽

Lung Weight ◽

Group Iii ◽

Group I ◽

Wet Weight

The efficacy of steroids in the treatment of acute aspiration pneumonia, following intratracheal kerosene instillation in primates, was examined. Forty Chacma baboons were utilized in three groups: group I (normal animals), group II (animals receiving 0.3 ml/kg intratracheal kerosene alone, control group), and group III (animals receiving 0.3 ml/kg intratracheal kerosene plus pre- and posttreatment with 5 mg/kg IMI dexamethasone). The lungs from all animals were examined macroscopically and microscopically and their lung wet weight-dry weight and lung weight-body weight ratios determined. On all parameters utilized, the lungs from groups II and III were different from group I. No statistical difference, however, could be detected between values obtained from groups II and III. These data tend to support the contention that steroids, even when given early, and in large doses, in the course of kerosene pneumonitis, do not alter the acute inflammatory process that occurs.

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Involvement of ovarian steroids and endogenous opioids in the fasting-induced suppression of pulsatile LH release in ovariectomized rats

Journal of Endocrinology ◽

10.1677/joe.0.1290321 ◽

1991 ◽

Vol 129 (3) ◽

pp. 321-328 ◽

Cited By ~ 121

Author(s):

F. R. A. Cagampang ◽

K.-I. Maeda ◽

H. Tsukamura ◽

S. Ohkura ◽

K. Ôta

Keyword(s):

Body Weight ◽

Opioid Peptides ◽

Endogenous Opioids ◽

Blood Sampling ◽

Ovariectomized Rats ◽

Opioid Antagonist ◽

Blood Samples ◽

Ovarian Steroids ◽

Naloxone Hydrochloride ◽

Lh Release

ABSTRACT The participation of the ovarian steroids and opioid peptides in the suppression of pulsatile LH release during acute fasting was examined in rats. Ovariectomized rats bearing silicone elastomer implants of oestradiol and/or progesterone were fasted for 48 h and subsequently blood samples were taken every 6 min for 3 h. Pulsatile LH release was suppressed after 48 h of fasting in the ovariectomized rats implanted with oestradiol but not in the oil-implanted controls. This suppression was enhanced after the administration of progesterone together with oestradiol. In a second experiment, ovariectomized rats bearing implants of oestradiol or oil were fasted for 48 h and injected s.c. (2·5 mg/kg body weight) with an opioid antagonist, naloxone hydrochloride, immediately before blood sampling. In the fasted oestradiol-treated ovariectomized rats, naloxone was able to prevent the suppression of pulsatile LH release. In the absence of oestradiol, however, naloxone was without effect on LH release in either the fasted or unfasted animals. These experiments indicate that the suppression of pulsatile LH release after 48 h of fasting is dependent upon oestradiol and that endogenous opioids are involved in the suppression. Journal of Endocrinology (1991) 129, 321–328

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Thyrotrophin-releasing hormone (TRH) and lung maturation

Reproduction Fertility and Development ◽

10.1071/rd9950443 ◽

1995 ◽

Vol 7 (3) ◽

pp. 443 ◽

Cited By ~ 7

Author(s):

GC Liggins

Keyword(s):

Fetal Lung ◽

Lung Maturation ◽

Rabbit Lung ◽

Glucocorticoid Treatment ◽

Fetal Sheep ◽

Thyrotrophin Releasing Hormone ◽

Releasing Hormone ◽

Fetal Plasma

Clinical trials of thyrotrophin-releasing hormone (TRH) in conjunction with antepartum glucocorticoid treatment in the prevention of respiratory distress syndrome is based on experimental evidence that fetal lung maturation is accelerated by exposure to raised concentrations of triiodothyronine (T3) in fetal plasma. Studies of fetal rat and rabbit lung in vitro show an inconsistent increase in surfactant synthesis in response to T3 and potentiation of the response to corticosteroid. Experiments with fetal rodents in vivo are difficult to interpret because of confounding effects of the procedures and the responses to T3 are variable. In fetal sheep, very high concentrations of T3 are without effect on lung maturation. These observations suggest that the action of TRH on the lung may be mediated at least in part by one of the numerous, non-hormonal pathways known to be stimulated by TRH, particularly the autonomic nervous system. Experiments in rats and sheep lend support to this possibility. It is concluded that available evidence is inadequate to determine the mechanism of action of TRH.

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EVIDENCE FOR INDEPENDENT REGULATORS OF ORGAN MATURATION IN FETAL RABBITS

PEDIATRICS ◽

10.1542/peds.47.1.57 ◽

1971 ◽

Vol 47 (1) ◽

pp. 57-64

Author(s):

Robert V. Kotas ◽

Barry D. Fletcher ◽

John Torday ◽

Mary Ellen Avery

Keyword(s):

Body Weight ◽

Gestational Age ◽

Single Injection ◽

Lung Maturation ◽

Lung Weight ◽

Stage Of Development ◽

Lung Age ◽

Ossification Centers ◽

Range Of Variation ◽

Lung Maturity

The degree of organ development bears a relationship to gestational age, but in a given infant not all organs need be at the same stage of development. The range of variation of organ maturation can be best studied in an animal with a large litter, such as the rabbit, in which gestation can be precisely timed. Body weight, ossification centers, and lung "maturity," defined as distensibility and stability on deflation, were all measured. Marked variations within a litter allowed study of the relationships between them. Body weight and the number of ossification centers were closely correlated at the same gestational age (R = 0.88, p 001). Ossification centers were less well correlated with gestational age. Lung "age," on the other hand, was more closely related to gestational age than body weight. A single injection of the fetus with 9-fluoroprednisolone, a glucocorticoid, at 24 days resulted in an acceleration of lung maturation, defined in terms of distensibility and the presence of surfactant by 26 to 27 days. No increase in lung weight took place. Similarly, the glucocorticoid had no effect on body size or the number of ossification centers, suggesting that regulators of maturation of these organs are independent.

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Quantitative Microscopic Comparison of the Organization of the Lung in Transgenic Mice Expressing Transforming Growth Factor-α (TGF-α)

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162533 ◽

1996 ◽

Vol 54 ◽

pp. 14-15

Author(s):

C. G. Plopper ◽

C. Helton ◽

A. J. Weir ◽

J. A. Whitsett ◽

T. R. Korfhagen

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Transgenic Mice ◽

Blood Vessels ◽

Lung Parenchyma ◽

Lung Maturation ◽

Alveolar Air ◽

Parenchymal Tissue ◽

Air Space ◽

Conducting Airways

A wide variety of growth factors are thought to be involved in the regulation of pre- and postnatal lung maturation, including factors which bind to the epidermal growth factor receptor. Marked pulmonary fibrosis and enlarged alveolar air spaces have been observed in lungs of transgenic mice expressing human TGF-α under control of the 3.7 KB human SP-C promoter. To test whether TGF-α alters lung morphogenesis and cellular differentiation, we examined morphometrically the lungs of adult (6-10 months) mice derived from line 28, which expresses the highest level of human TGF-α transcripts among transgenic lines. Total volume of lungs (LV) fixed by airway infusion at standard pressure was similar in transgenics and aged-matched non-transgenic mice (Fig. 1). Intrapulmonary bronchi and bronchioles made up a smaller percentage of LV in transgenics than in non-transgenics (Fig. 2). Pulmonary arteries and pulmonary veins were a smaller percentage of LV in transgenic mice than in non-transgenics (Fig. 3). Lung parenchyma (lung tissue free of large vessels and conducting airways) occupied a larger percentage of LV in transgenics than in non-transgenics (Fig. 4). The number of generations of branching in conducting airways was significantly reduced in transgenics as compared to non-transgenic mice. Alveolar air space size, as measured by mean linear intercept, was almost twice as large in transgenic mice as in non-transgenics, especially when different zones within the lung were compared (Fig. 5). Alveolar air space occupied a larger percentage of the lung parenchyma in transgenic mice than in non-transgenic mice (Fig. 6). Collagen abundance was estimated in histological sections as picro-Sirius red positive material by previously-published methods. In intrapulmonary conducting airways, collagen was 4.8% of the wall in transgenics and 4.5% of the wall in non-transgenic mice. Since airways represented a smaller percentage of the lung in transgenics, the volume of interstitial collagen associated with airway wall was significantly less. In intrapulmonary blood vessels, collagen was 8.9% of the wall in transgenics and 0.7% of the wall in non-transgenics. Since blood vessels were a smaller percentage of the lungs in transgenics, the volume of collagen associated with the walls of blood vessels was five times greater. In the lung parenchyma, collagen was 51.5% of the tissue volume in transgenics and 21.2% in non-transgenics. Since parenchyma was a larger percentage of lung volume in transgenics, but the parenchymal tissue was a smaller percent of the volume, the volume of collagen associated with parenchymal tissue was only slightly greater. We conclude that overexpression of TGF-α during lung maturation alters many aspects of lung development, including branching morphogenesis of the airways and vessels and alveolarization in the parenchyma. Further, the increases in visible collagen previously associated with pulmonary fibrosis due to the overexpression of TGF-α are a result of actual increases in amounts of collagen and in a redistribution of collagen within compartments which results from morphogenetic changes. These morphogenetic changes vary by lung compartment. Supported by HL20748, ES06700 and the Cystic Fibrosis Foundation.

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