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At least 559 records · Page 31Linked to original sources
PubMed1997

Direct modulation of G-proteins by polyunsaturated fatty acids: a novel eicosanoid-independent regulatory mechanism in the developing lung.

Basal and fatty-acid-modulated G-protein function was studied in 1-3-day-pre-term, fetal guinea-pig, type II (fATII) pneumocyte apical membrane. Unstimulated (tonic) high-affinity GTPase activity (measured as [gamma-32P]GTP hydrolysis rate) was high and 77% pertussis toxin-insensitive. Alteration of this activity was used as a marker of G-protein regulation. Arachidonic acid (AA) showed a dose-dependent (IC50 = 48+/-8 microM) inhibition of activity at concentrations significantly below critical micellar concentrations; this effect was mimicked by other polyunsaturated fatty acids (IC50 for linoleic acid = 47 +/- 2 microM; IC50 for oleic acid = 106 +/- 11 microM). Saturated fatty acids showed no effect. The effect of AA on ouabain-insensitive ATPases in the same preparation was significantly lower, suggesting a specificity of the GTPase modulation effect. AA modulation of GTPase activity was not attenuated by blocking eicosanoid metabolism with inhibitors of 5'-lipoxygenase, cyclo-oxygenase and P-450. In order to explore further the mechanism of AA-G-protein interaction, the effect of AA on the time course and equilibrium binding of [35S]GTP[S] to apical membrane was studied. Consistent with our GTPase assay data, AA inhibited binding with an IC50 value of 71+/-1 microM; stearic acid did not mimic this effect. This is the first report of unsaturated-fatty-acid-specific modulation of lung G-protein function: since AA also up-regulates perinatal lung alveolar Na+ transport, we suggest this lipid/G-protein switch helps maintain pulmonary fluid homoeostasis around birth.

Animals↗
PubMed1994

Do insults to the developing lung increase the incidence of wheezing in infants.

This study reports on the possible role of perinatal and early infantile factors in the aetiology of the 'wheezy baby syndrome'. Over a 2 year period we recruited 150 infants from the outpatients department who had a typical wheezing attack, with chest X-ray showing only hyperinflation and non-specific increased markings, and who had been born in hospital with available perinatal and postnatal records. One hundred and fifty control infants were also recruited. A retrospective study was then undertaken comparing the two groups of infants for the incidence of neonatal problems and the incidence of previous lower respiratory tract infections. The results showed that 40 per cent of cases had previously had meconium aspiration syndrome compared with only 2.6 per cent of controls, and that 26.6 per cent of cases had previously had at least one lower respiratory tract infection compared with 5.3 per cent of controls. Other factors, including the incidence of transient tachypnea, and personal and family history of atopy, showed no significant trends. Meconium aspiration syndrome and lower respiratory tract infections are important aetiological factors in the pathogenesis of 'wheezy baby syndrome', rather than inheritance of atopic diathesis.

Diagnosis-Related Groups↗
PubMed1981

Epithelial solute permeability, ion transport and tight junction morphology in the developing lung of the fetal lamb.

1. Experiments were performed on exteriorized fetal lambs of between 69 days' gestation and term (147 days) in order to observe changes in lung volume and lung liquid secretion rate, and to delineate any alterations in solute permeability, ion transport and tight junction morphology in the maturing lung epithelium. Whilst it was technically possible to measure solute permeability as early as 69 days it was not feasible to apply the Ussing flux ratio technique before 84 days.2. Fetal lung liquid volume and secretion rate, when normalized for body weight, increase linearly with gestation, whereas tracheal volume expressed in the same manner remains constant.3. When expressed in terms of pore theory, epithelial permeability to small polar non-electrolytes does not change between 69 days and term (equivalent pore radius 0.66 nm and 0.64 nm respectively).4. In the immature fetus of 69-76 days, mean epithelial tight junction strand number is 8.3, whereas by the end of gestation it has fallen to 4.6.5. The transfer constants (min(-1)) for sodium and chloride movement in the direction lung liquid to plasma are, respectively, some 6 and 4 times greater at 84-87 days than at term.6. As in the mature fetus, the lung epithelium at 84-87 days actively transports chloride from plasma to lung lumen, albeit with a slightly reduced transport e.m.f. Sodium movement does not, at any gestational age, differ from the predictions for passive transfer.7. In lung liquid the concentrations of chloride and potassium increase and that of bicarbonate decreases during gestation, whilst that of sodium does not change. The rises in lung liquid chloride and potassium concentrations follow those in plasma, maintaining plasma/lung liquid ratios of 0.7 and 0.95 respectively. However, plasma bicarbonate remains constant and the plasma/lung liquid ratio for bicarbonate rises from 3 at 69-76 days to 20 near term as the lung liquid bicarbonate falls from 9.8 to under 2 m-mole kg(-1) H(2)O.8. Whereas lung liquid protein concentration remains constant and low at about 0.35 g l.(-1), plasma protein concentration rises from 23 g l.(-1) at 69-76 days to 43 g l.(-1) near term. During the same period arterial blood pressure doubles.

Animals↗
PubMed1997

Effect of hyperoxia on substance P expression and airway reactivity in the developing lung.

This study was undertaken to characterize changes in the tachykinin system induced by hyperoxic exposure and the potential effects on airway contractile responses. We exposed 7-day-old rat pups to either room air or hyperoxia (> 95% O2) for 7 days to assess pulmonary beta-preprotachykinin (beta-PPT) gene expression, substance P (SP) levels, and airway contractile responses to cholinergic stimulation before and after neurokinin-1 (NK1) receptor blockade. Lung beta-PPT mRNA expression, lung and tracheal SP levels, and contractile responses to exogenous acetylcholine and electrical field stimulation were measured in vitro in normoxia- and hyperoxia-exposed tracheal cylinders. Hyperoxia caused a 1.1- to 2.6-fold increase in steady-state lung beta-PPT mRNA and a 50 and 32% increase in SP levels of lung and trachea, respectively. In response to cholinergic stimulation, maximal contractile force (Emax) of hyperoxia exposed tracheal muscle was significantly higher than for normoxic controls. Addition of the SP (NK1) receptor blocker CP-99994 (10 microM) decreased sensitivity to electrical field stimulation in both hyperoxic and normoxic trachea without a significant decline in Emax. These data provide evidence for both increased SP production and enhanced maximal contractile responses of hyperoxia-exposed neonatal trachea to cholinergic stimulation. The tachykinin peptide SP does not, however, appear to play a major role in the enhanced airway reactivity associated with hyperoxic lung injury during early postnatal life.

Acetylcholine↗
PubMed1985

Factors related to the appearance of alveolar macrophages in the developing lung.

The numbers of alveolar macrophages (AM) are known to be low in utero and to increase rapidly after birth. This study analyzed factors related to the appearance of AM in the lungs of term and preterm monkeys (Macaca nemestrina). We found that the numbers of AM were greater at birth in term than in preterm monkeys (p less than 0.01) and that they increased with postnatal age in term animals (r = 0.86) and in preterm animals without hyaline membrane disease (HMD) (r = 0.79). In contrast, the numbers of AM did not increase with postnatal age in preterm animals with HMD (r = 0.17). By multivariant analysis, AM numbers correlated most strongly with a combination of 2 variables: lavage fluid phospholipid and absence of HMD (r = 0.996). Preparations of alveolar surface-active material from newborn monkeys and to a lesser degree from adult monkeys were found to stimulate migration and polarization of monkey AM and blood monocytes in vitro. The migration-stimulating factor(s) in alveolar surface-active material had an apparent molecular weight greater than 10,000 and appeared not to be a lipoxygenase product of arachidonic acid metabolism. These data indicate a correlation between factors regulating lung pressure-volume stability and AM numbers and are consistent with a potential role for components of alveolar surface-active material in regulating the perinatal increase in AM.

Aging↗
PubMed1993

Sensitive periods for glucocorticoids' regulation of Na+,K(+)-ATPase mRNA in the developing lung and kidney.

We have previously reported that in the infant rat renal cortex, a saturating dose of glucocorticoid hormones (GC) rapidly increases the abundance of Na+,K(+)-ATPase mRNA. We now show that this effect is dose dependent. In the renal cortex of 10-d-old rats, an increase in renal Na+,K(+)-ATPase mRNA occurs with 2.5 micrograms betamethasone/100 g body weight. In subsequent experiments, performed 6 h after a saturating dose (60 micrograms/100 g body weight), we show that the effect is age dependent. The most marked effects on renal cortical alpha-mRNA were found at 10 d of age (5.3- +/- 0.9-fold). A significant increase was also found in 20-d-old rats (1.6- +/- 0.2-fold), but no effect was found in fetal and 5-d-old rats. Studies were also performed on the lung, where the most marked effect was noted in the perinatal period (2.0- +/- 0.1-fold 2 d before birth and 1.76 +/- 0.2 at 5 d of age), but no effect on alpha-mRNA was found at 10 and 20 d. In one protocol, the effect of betamethasone on renal Na+K(+)-ATPase mRNAs abundance was determined in adult adrenalectomized rats. In these rats, betamethasone induced a significant 1.6- +/- 0.2-fold and 1.8- +/- 0.3-fold increase in renal Na+,K(+)-ATPase mRNA. This effect, however, was significantly smaller than the increase induced in intact 10-d-old rats. GC induction of Na+,K(+)-ATPase mRNA is age and tissue dependent and is dependent on factors other than GC-receptor availability. The GC-sensitive period appears to coincide with the physiologic need for organ maturation.

Age Factors↗
PubMed1996

Oxygen toxicity to the developing lung of the mouse: role of reactive oxygen species.

Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful were N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase); N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.

Analysis of Variance↗
PubMed1975

Phospholipid biosynthesis: the activity of phosphatidic acid phosphohydrolase in the developing lung and amnionic fluid.

The presented data suggest that PAPase may, indeed, be important in the biosynthesis of lung phospholipids. The observed increase in the specific activity of rabbit lung precedes the "surge" of phosphatidylcholine concentration and surfactant biosynthesis by at least 24 hours. In human amnionic fluid, PAPase specific activity was markedly increased in pregnancies of 35 weeks of gestation or more. The increase in the specific activity of PAPase preceded the "surge" of acetone precipitated phosphatidylcholine. The reported studies may provide an additional procedure to examine the problems associated with surfactant biosynthesis.

Amniotic Fluid↗
PubMed1999

Risk of developing lung cancer in relation to exposure to fumes from Chinese-style cooking.

In an evaluation of the association between exposure to indoor air pollution from Chinese-style cooking and the risk of lung cancer, epidemiologic and experimental studies were reviewed. The 9 case-referent studies that were identified showed consistent positive associations between the risk of lung cancer and a variety of indices of exposure to indoor air pollution arising from Chinese-style cooking. Three experimental studies showed that volatile emissions from oils heated in woks are mutagenic in several in vitro short-term test systems. Several toxic agents, including some accepted or suspected carcinogens, have been detected in the emissions of the heated cooking oils. While experimental data support the epidemiologic data, it may be premature to conclude that the association is causal. However, simple precautions can be taken to reduce the risk in the event that exposure to indoor air pollution arising from Chinese-style cooking is indeed a cause of lung cancer.

Air Pollution, Indoor↗