Role of cyclic AMP and related enzymes in rat lung growth and development

Ms, Nijjar

doi:10.1016/0304-4165(79)90036-9

Cited by 23 publications

(9 citation statements)

References 33 publications

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“…lc, d), thus confirming our previous observations [24,25]. However, data on the pregnant rat before and after par turition were interesting in that the basal ade- Adenylate cyclase activity was assayed as described un der Materials and Methods.…”

Section: Discussionsupporting

confidence: 73%

“…Aminophylline has also been shown to enchance fetal lung matura tion and appears to act via cyclic AMP as it prevents degradation of cyclic AMP by in hibiting cyclic AMP phosphodiesterase [17,19]. However, there is a little previous evi dence indicating that glucocorticoids act on fetal lungs via cyclic AMP [2,3], We and others have shown previously that an elevation in fetal lung cyclic AMP activates the cascade enzymes to promote glycogenolysis, thereby providing glycolytic intermediates for the synthesis of surfactant phospholipids [22,24], Cyclic AMP levels in developing rat lungs are dependent on the relative activities of adenylate cyclase and cyclic phosphodiesterase which are regulated by the intracellular modulators such as the activator protein and calmodulin, respec tively [24,25]. However, direct effects of glu cocorticoids on the activities of these en zymes has not been examined.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Dexamethasone Administration to Pregnant Rats on Adenylate Cyclase and Cyclic AMP Phosphodiesterase Activities in the Maternal and Fetal Lungs

Chaudhary¹,

Nijjar²

1984

Neonatology

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Adenylate cyclase and cyclic AMP phosphodiesterase activities were examined in the maternal and fetal lungs before and after delivery from the saline- and dexamethasone-treated pregnant rats. Basal adenylate cyclase activity in the maternal lungs of control animals did not change after parturition whereas the enzyme activity in fetal lungs increased 2.5-fold after birth. Dexamethasone treatment reduced adenylate cyclase activity in the maternal lungs before and after parturition while the enzyme activity in fetal lungs was increased. The ability of the cytoplasmic factors to activate adenylate cyclase in maternal lungs decreased after parturition. Dexamethasone treatment of the pregnant rat lowered the cytoplasmic activation of the maternal enzyme before and after parturition, but the percent activation of the enzyme in both the maternal and fetal lungs was not affected. The decrease in activator activity of the maternal lungs after parturition was not apparently due to the reduced sensitivity of adenylate cyclase to the same level of the activator protein. However, it would appear that both adenylate cyclase and its activator protein have undergone some maturational changes during lung development. Adrenalectomy of rats did not alter the basal adenylate cyclase activity in lung membranes but reduced the cytoplasmic activation of the enzyme. Unlike pregnant rats, dexamethasone treatment of adrenalectomized rats restored the cytoplasmic activation of adenylate cyclase not only to the control value, but potentiated it even higher than the control without affecting the basal adenylate cyclase activity. Cyclic AMP phosphodiesterase activity in both the maternal and fetal lungs was not influenced by parturition. However, dexamethasone treatment lowered cyclic AMP phosphodiesterase activity in both the maternal and fetal lungs at both ages. Dexamethasone treatment of pregnant rats elevated phospholipids and lowered DNA levels in the maternal as well as fetal lungs. These data are consistent with the view that dexamethasone treatment of pregnant rats during late gestation may elevate cyclic AMP levels to induce fetal lung maturation with a concomitant decrease in cellular proliferation.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Effects of Dexamethasone Administration to Pregnant Rats on Adenylate Cyclase and Cyclic AMP Phosphodiesterase Activities in the Maternal and Fetal Lungs

Chaudhary¹,

Nijjar²

1984

Neonatology

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“…In animals with induced diabetes, decreased enzyme activities have been observed in fetal lung only when the mother was severely diabetic (200,253), a condition in which the fetuses are generally not hyperinsulinemic. Indications of a possible adverse effect of excessive insulin upon lung phospholipid biosynthesis have been gained exclusively from in vitro experiments.…”

Section: Direct Impairment Of Surfactant Biosynthesis And/or Secretiomentioning

confidence: 97%

“…In fact, the effect of corticosteroids could be indirect. It has been shown that aminophylline, an inhibitor of phosphodiesterase which enhances cellular cyclic AMP levels, and cyclic AMP itself, stimulate both glycogenolysis and the synthesis of phospholipids in fetal rat or rabbit lung in vivo and in vitro (17,172,200,233). Corticosteroids have been shown to inhibit phosphodiesterase activity and to increase cyclic AMP concentration in rabbit fetal lung (1 7), and to increase the number of P-adrenergic receptors in rat fetal lung explants in vitro (170).…”

Section: Cdp Cholinementioning

confidence: 98%

Fetal Lung Development in the Diabetic Pregnancy

1985

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It seems quite likely that the normal process of fetal lung biochemical maturation is delayed by maternal diabetes and that abnormalities in the pulmonary surfactant system are involved. The appearance of PG in amniotic fluid and possibly in fetal lung is impaired or at least delayed. The same is possibly true for DSPC, the main constituent of surfactant, but recent discrepant data call for further clarification of this specific point. Careful determination of the fetal lung phospholipid profile by amniotic fluid analysis helps predict and prevent RDS in IDM, along with a careful control of the maternal diabetic condition. A study of alveolar surfactant at birth, if it could be performed in addition to amniotic fluid analysis, would help to better characterize surfactant deficiency in IDM. On the basis of both in vivo and in vitro experimental approaches, it seems clear that hyperglycemia and fetal reactional hyperinsulinism are both involved in the processes delaying fetal lung maturation. Further advances in the understanding of cellular and molecular mechanisms leading to this delay will be conditional on the availability of animal models reproducing the features of the metabolic and hormonal environment of human fetuses in diabetic pregnancies. The appropriateness of in vivo models needs to be defined by two kinds of criteria: 1) presence of simultaneous hyperglycemia and hyperinsulinemia in the fetus; 2) the presence of delayed fetal lung maturation as judged by morphology and morphometry of epithelial lung cells, by physiological assessment of surfactant, and by the phospholipid composition of the lung (and including lung tissue per se, bronchoalveolar lavage fluid, lamellar bodies, and/or isolated surfactant fractions). Therefore, future studies must necessarily be comprehensive in scope and include information indicating that fetal growth, blood glucose, and circulating insulin are all increased. Such models already exist in rats and rabbits. Rat models are possibly not the best because of the high basal level of fetal blood insulin in this species and the relatively rapid rate of lung maturation that is not analogous to the human. Monkey models are of interest, because of their close relationship with the human pregnancy, and need to be studied further. They are particularly attractive also because primary fetal hyperinsulinism can be studied (268), as well as the combination of hyperglycemia and hyperinsulinemia in pregnancies of STZ-treated monkeys (152). An appropriate model of the diabetic pregnancy could provide answers to the following questions. Are the biosynthetic pathways of surfactant phospholipids directly impaired?(ABSTRACT TRUNCATED AT 400 WORDS)

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“…The PDE superfamily currently consists of 11 family members with differing selectivity for cAMP and/or cGMP [11]. Several PDEs are abundant in neonatal and adult lung tissue [13,14], including PDE1, PDE4 and PDE5 isoforms [11]. The documented roles for PDE5 in vascular homeostasis resulted in the evaluation of PDE5 inhibitors for the treatment of disorders with a vascular component, including PH [15,16] and BPD [17].…”

mentioning

confidence: 99%

Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia

Woyda¹,

Koebrich²,

Reiss³

et al. 2008

Eur Respir J

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Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD.The aim of the present study was to investigate PDE expression in the lung of hyperoxiaexposed mice, and to assess the viability of PDE4 as a therapeutic target in BPD.Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement and increased septal wall thickness. Changes were evident after 14 days and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level, PDE1A and PDE4A were upregulated while PDE5A was downregulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg?kg) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area and improved dynamic lung compliance.Pharmacological inhibition of phosphodiesterase improved lung alveolarisation in hyperoxiainduced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.

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Role of cyclic AMP and related enzymes in rat lung growth and development

Cited by 23 publications

References 33 publications

Effects of Dexamethasone Administration to Pregnant Rats on Adenylate Cyclase and Cyclic AMP Phosphodiesterase Activities in the Maternal and Fetal Lungs

Effects of Dexamethasone Administration to Pregnant Rats on Adenylate Cyclase and Cyclic AMP Phosphodiesterase Activities in the Maternal and Fetal Lungs

Fetal Lung Development in the Diabetic Pregnancy

Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia

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