Abolition of Fetal Breathing Movements by Spinal Cord Transection Leads to Reductions in Fetal Lung Liquid Volume, Lung Growth, and IGF-II Gene Expression

Our aim was to determine the role of fetal breathing movements (FBM) in the maintenance of fetal lung liquid volume. Experiments were performed in 14 chronically catheterized fetal sheep. FBM were selectively abolished for 48 h by the infusion of tetrodotoxin (TTX) onto the phrenic nerves of five fetuses. Lung liquid volumes and secretion rates were measured before each treatment, 46–48 h after the start of the TTX infusion, and 22–24 h after the end of the infusion. Blockade of the phrenic nerves reduced fetal lung liquid volumes from 27.6 +/- 1.9 to 21.8 +/- 2.6 ml/kg and increased lung liquid secretion rates from 3.8 +/- 0.6 to 6.2 +/- 1.1 ml.h-1.kg-1. Control experiments confirmed the lack of effect of TTX infused intravenously and saline infused intrapleurally on changes in fetal lung liquid volume and secretion rate. To measure the static relaxation volume of the fetal lung, in six fetuses we combined skeletal muscle paralysis with bypass of the upper airway for 48 h. This reduced fetal lung liquid volume from 39.1 +/- 3.1 to 23.0 +/- 2.5 ml/kg and increased lung liquid secretion rates from 4.1 +/- 0.7 to 5.8 +/- 0.9 ml.h-1.kg-1. This experiment demonstrates that the fetal lung is normally maintained at a level of expansion that is much greater than its static relaxation volume. We conclude that the volume of luminal liquid in the fetal lungs is dependent on the diaphragmatic contractions associated with FBM. Their effect is to resist the elastic recoil of the fetal lungs, thereby reducing the loss of liquid from the lungs via the trachea.

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Fetal breathing and pressures in the trachea and amniotic sac during oligohydramnios in sheep

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.1.293 ◽

1991 ◽

Vol 70 (1) ◽

pp. 293-299 ◽

Cited By ~ 11

Author(s):

K. A. Dickson ◽

R. Harding

Keyword(s):

Amniotic Fluid ◽

Flow Rate ◽

Pressure Fluctuations ◽

Fetal Lung ◽

Lung Hypoplasia ◽

Liquid Volume ◽

Fetal Sheep ◽

Tracheal Pressure ◽

Fetal Breathing ◽

Lung Liquid

Oligohydramnios commonly leads to fetal lung hypoplasia, but the mechanisms are not fully understood. Our aim was to determine, in fetal sheep, the effects of prolonged oligohydramnios on the incidence and amplitude of tracheal pressure fluctuations associated with fetal breathing movements (FBM), on tracheal flow rate during periods of FBM (VtrFBM) and periods of apnea (Vtrapnea), on tracheal pressure relative to amniotic sac pressure, and on amniotic sac pressure relative to atmospheric pressure. In five sheep, oligohydramnios was induced by draining amniotic and allantoic fluids from 107 to 135 days of gestation (411.8 +/- 24.4 ml/day), resulting in fetal lung hypoplasia. In five control sheep, amniotic fluid volume was 732.3 +/- 94.4 ml. Oligohydramnios increased the incidence of FBM by 14% at 120 and 125 days and the amplitude of FBM by 30–34% at 120–130 days compared with controls. From 120 days onward, VtrFBM was 35–55% lower in experimental fetuses than in controls. Influx of lung liquid during FBM was 87% lower in experimental fetuses than in controls. Vtrapnea, tracheal pressure, and amniotic sac pressure were not significantly altered by oligohydramnios. Our tracheal flow rate data suggest that transient changes in lung liquid volume during periods of FBM and periods of apnea were diminished by oligohydramnios. We conclude that the primary factor in the etiology of oligohydramnios-induced lung hypoplasia is not an inhibition of FBM (as measured by tracheal pressure fluctuations) or a reduction in amniotic fluid pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

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Changes in lung expansion alter pulmonary DNA synthesis and IGF-II gene expression in fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.265.4.l403 ◽

1993 ◽

Vol 265 (4) ◽

pp. L403-L409 ◽

Cited By ~ 24

Author(s):

S. B. Hooper ◽

V. K. Han ◽

R. Harding

Keyword(s):

Gene Expression ◽

Dna Synthesis ◽

Fetal Lung ◽

Liquid Volume ◽

Mrna Levels ◽

Pulmonary Tissue ◽

Fetal Sheep ◽

Tracheal Obstruction ◽

Lung Expansion ◽

Lung Liquid

Our aim was to determine the effect of short-term (7 days) alterations in fetal lung liquid volume on pulmonary DNA synthesis rates and insulin-like growth factor-II (IGF-II) mRNA levels. Fifteen chronically catheterized fetal sheep were divided into three groups. In one, the trachea was obstructed, in another lung liquid was drained by gravity, and the third group served as controls. After 7 days, [3H]thymidine was injected into each fetus and 8 h later fetal tissues were collected. Fetal lung-to-body weight ratios and total lung DNA contents were greatly increased in fetuses with tracheal obstruction compared with control fetuses, whereas the drainage of lung liquid did not affect these measurements. DNA synthesis rates in pulmonary tissue were significantly reduced from a mean control value of 153.3 +/- 25.1 disintegrations per minute (dpm)/microgram DNA to 57.2 +/- 8.6 dpm/microgram DNA by lung liquid drainage (P < 0.05) and were significantly increased to 236.0 +/- 24.0 dpm/microgram DNA by tracheal obstruction (P < 0.05). Following tracheal obstruction, lung IGF-II mRNA levels were increased to 177.0 +/- 18.2% (P < 0.05) of the mean value for control fetuses, whereas they were reduced to 56.1 +/- 7.1% of control in lung liquid-drained fetuses. We conclude that altering fetal lung expansion has a potent and rapid effect on pulmonary DNA synthesis and that this effect may, in part, be mediated by an alteration in IGF-II gene expression.

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Physiological factors in fetal lung growth

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y88-184 ◽

1988 ◽

Vol 66 (8) ◽

pp. 1122-1128 ◽

Cited By ~ 29

Author(s):

Joseph A. Kitterman

Keyword(s):

Blood Flow ◽

Fetal Lung ◽

Volume Of Fluid ◽

Growth Potential ◽

Physical Factors ◽

Lung Growth ◽

Pulmonary Tissue ◽

Tracheal Pressure ◽

Fetal Breathing ◽

Fetal Breathing Movements

Adequate pulmonary function at birth depends upon a mature surfactant system and lungs of normal size. Surfactant is controlled primarily by hormonal factors, especially from the hypophysis, adrenal, and thyroid; but these have little influence on fetal lung growth. In contrast, current data indicate that lung growth is determined by the following physical factors that permit the lungs to express their inherent growth potential. (a) Adequate intrathoracic space: lesions that decrease intrathoracic space impede lung growth, apparently by physical compression. (b) Adequate amount of amniotic fluid: oligohydramnios retards lung growth, possibly by lung compression or by affecting fetal breathing movements or the volume of fluid within the potential airways and airspaces. (c) Fetal breathing movements of normal incidence and amplitude: fetal breathing movements stimulate lung growth, possibly by stretching the pulmonary tissue, and do not affect mean pulmonary blood flow but do induce small changes in phasic flow; these changes are probably too slight to influence lung growth. (d) Normal balance of volumes and pressures within the potential airways and airspaces: in the fetus, tracheal pressure > amniotic pressure > pleural pressure. This differential produces a distending pressure which may promote lung growth. Disturbing the normal pressure relationships alters the volume of fluid in the lungs and distorts lung growth, which is stimulated by distending the lungs and is impeded by decreasing lung fluid volume. The mechanisms by which these factors affect lung growth remain to be defined. Fetal lung growth also depends on at least a small amount of blood flow through the pulmonary arteries. Although a modest reduction in flow (to 85% of control) does not affect lung growth, total obstruction of the pulmonary artery impairs lung growth. Thus, bronchial blood flow alone is insufficient to supply the nutritional demands of the growing fetal lung.

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Changes in lung liquid dynamics induced by prolonged fetal hypoxemia

Journal of Applied Physiology ◽

10.1152/jappl.1990.69.1.127 ◽

1990 ◽

Vol 69 (1) ◽

pp. 127-135 ◽

Cited By ~ 34

Author(s):

S. B. Hooper ◽

R. Harding

Keyword(s):

Amniotic Fluid ◽

Fetal Lung ◽

Liquid Volume ◽

Uterine Blood Flow ◽

Fetal Sheep ◽

Fetal Breathing Movements ◽

Before And After ◽

Normoxic Control ◽

Lung Liquid ◽

Liquid Dynamics

Our aim was to determine the effect of prolonged fetal hypoxemia, induced by reduced maternal uterine blood flow (RUBF), on fetal lung liquid secretion, flow, and volume. In chronically catheterized fetal sheep, lung liquid volume (VL) and the secretion rate of lung liquid (Vs) were measured before and after a 24-h period of either RUBF or normoxemia. Tracheal fluid flow and the incidence of fetal breathing movements (FBM) were measured before, during, and after the 24-h period. In normoxic control fetuses Vs was not significantly altered. After 24 h of RUBF, Vs was significantly (P less than 0.005) reduced compared with pre-RUBF values. During 24 h of RUBF the incidence of FBM declined initially but returned to control values after 12-16 h. In seven of eight fetuses, over the 12- to 24-h period of RUBF, large amounts of liquid (22.7-62.6 ml) were drawn into the lungs during FBM, resulting in a net movement of amniotic fluid into the lungs. During the 18- to 24-h period of RUBF, changes in the incidence of FBM were found to be significantly and positively correlated (r = 0.86, P less than 0.005) with the changes in VL that occurred over the 24-h period. Thus, prolonged RUBF can result in the inhalation of large volumes of amniotic fluid by the fetus, which could be a cause of in utero meconium aspiration.

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Decline in lung liquid volume before labor in fetal lambs

Journal of Applied Physiology ◽

10.1152/jappl.1986.61.6.2266 ◽

1986 ◽

Vol 61 (6) ◽

pp. 2266-2272 ◽

Cited By ~ 50

Author(s):

K. A. Dickson ◽

J. E. Maloney ◽

P. J. Berger

Keyword(s):

Regression Analysis ◽

Flow Rate ◽

Fetal Lung ◽

Indicator Dilution ◽

Liquid Volume ◽

Confidence Limits ◽

Least Squares Regression ◽

Dilution Technique ◽

Pulmonary Epithelium ◽

Lung Liquid

The volume of liquid in the fetal lung depends on the amount of liquid secreted across the pulmonary epithelium and the amount flowing through the trachea. Lung liquid volume (V1) and secretion rate Vs) were determined using an indicator-dilution technique, while tracheal flow rate (Vtr) was measured simultaneously with a bubble flowmeter. Least-squares regression analysis showed that in 10 chronically instrumented fetal lambs, V1 increased from 51.0 ml at 119 days to 104.6 ml at 135 days (V1 = -347.65 + 3.35 X days; 95% confidence limits on slope: 1.89–4.81) before declining to 70.2 ml at 142 days gestation (V1 = 768.8 – 4.92 X days; 95% confidence limits on slope: -2.55 to -7.30). Similarly Vs increased from 7.4 ml/h at 119 days to 16.8 ml/h at 133 days (Vs = -72.35 + 0.67 X days; 95% confidence limits on slope: 0.21–1.14), before declining to 7.1 ml/h at 142 days (Vs = 159.07 – 1.07 X days; 95% confidence limits on slope: -0.56 to -1.57). Vtr did not change significantly with gestation. We conclude that V1 increases until 135 days gestation, after which it falls substantially. This fall in volume, which occurs well before the onset of labor, results predominantly from the decline in Vs.

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Influence of growth hormone on the lung growth response to tracheal obstruction in fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.278.3.l453 ◽

2000 ◽

Vol 278 (3) ◽

pp. L453-L459 ◽

Cited By ~ 6

Author(s):

L. Nardo ◽

I. R. Young ◽

S. B. Hooper

Keyword(s):

Growth Hormone ◽

Dna Content ◽

Fetal Lung ◽

Control Group ◽

Lung Growth ◽

Lung Weight ◽

Fetal Sheep ◽

Tracheal Obstruction ◽

Lung Expansion ◽

Lung Liquid

Obstructing the fetal trachea is a potent stimulus for fetal lung growth, but little is known about the factors that regulate this process. Our aim was to determine the role of growth hormone (GH) in regulating the increase in lung growth induced by obstruction of the trachea in fetal sheep. Twenty chronically catheterized fetal sheep, nine of which were hypophysectomized, were divided into four experimental groups: 1) control group ( n = 4), 2) a group in which the fetal trachea was obstructed for 3 days (3-day obstructed; n = 6), 3) a 3-day obstructed group in which the pituitary was removed [hypophysectomized (HX)] and the fetus was given maintenance infusions of ACTH, thyroxine, and human GH (hGH; HX hGH 3-day obstructed; n = 5), and 4) a HX 3-day obstructed group in which the fetus was given maintenance infusions of ACTH and thyroxine ( n = 5). Tracheal obstruction significantly increased fetal lung liquid volumes from 37.2 ± 3.2 ml/kg in control fetuses to 75.6 ± 9.0 ml/kg in 3-day obstructed fetuses, and the presence or absence of GH did not affect this increase. Similarly, the presence or absence of GH did not affect the increase in lung weight or protein content induced by 3 days of tracheal obstruction. However, in the absence of GH, 3 days of tracheal obstruction failed to increase total lung DNA content above unobstructed control values (107.9 ± 5.3 and 94.1 ± 7.0 mg/kg for control and HX 3-day obstructed groups, respectively). In contrast, 3 days of tracheal obstruction increased total lung DNA content to a similar extent in fetuses with an intact pituitary and HX fetuses that received GH replacement (126.0 ± 4.4 and 126.7 ± 4.0 mg/kg for 3-day obstructed and HX hGH 3-day obstructed groups, respectively). These data indicate that the absence of GH either abolishes or delays the acceleration in cell division caused by an increase in fetal lung expansion.

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Effects of elevated fetal cortisol concentrations on the volume, secretion, and reabsorption of lung liquid

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.269.4.r881 ◽

1995 ◽

Vol 269 (4) ◽

pp. R881-R887 ◽

Cited By ~ 9

Author(s):

M. J. Wallace ◽

S. B. Hooper ◽

R. Harding

Keyword(s):

Plasma Cortisol ◽

Fetal Lung ◽

Liquid Volume ◽

Fetal Sheep ◽

Fetal Plasma ◽

Age Related ◽

Lung Liquid ◽

Secretion Rates ◽

Related Increase

We have examined the role of cortisol in the gestational age-related increase in the ability of epinephrine to inhibit the secretion and induce the reabsorption of fetal lung liquid. Chronically catheterized fetal sheep were infused with either saline (n = 6) or increasing doses of cortisol (1.5-3.5 mg/day; n = 6) between 120 and 130 days of gestation (term approximately 145 days). Lung liquid volumes and secretion rates were measured at 120 days (before infusion) and at 125 days, and then at 130 days we tested the ability of epinephrine to inhibit lung liquid secretion and induce liquid reabsorption. Cortisol infusions increased fetal plasma cortisol and 3,5,3'-triiodothyronine (T3) concentrations to levels observed just before labor and significantly increased the age-related increase in fetal lung liquid volume and secretion rate. At 130 days, epinephrine caused a significantly greater rate of lung liquid reabsorption in cortisol-infused fetuses (10.3 +/- 2.3 ml/h) than in saline-infused fetuses (1.5 +/- 1.6 ml/h). We conclude that a premature elevation in circulating fetal cortisol concentrations, probably in conjunction with elevated T3 concentrations, prematurely increases the epinephrine-induced reabsorption of fetal lung liquid. It is likely, therefore, that the preparturient increase of fetal cortisol concentrations plays an important role in the clearance of lung liquid at birth.

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Dibutyryl cAMP induces a gestation-dependent absorption of fetal lung liquid

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.5.2054 ◽

1990 ◽

Vol 68 (5) ◽

pp. 2054-2059 ◽

Cited By ~ 57

Author(s):

D. V. Walters ◽

C. A. Ramsden ◽

R. E. Olver

Keyword(s):

Fetal Lung ◽

Liquid Volume ◽

Intracellular Camp ◽

Maximal Effect ◽

Dibutyryl Camp ◽

Rate Limiting Step ◽

Liquid Absorption ◽

Dependent Absorption ◽

Lung Liquid ◽

Rate Limiting

The maturation of the adenosine 3′,5′-cyclic monophosphate-(cAMP) dependent pathway controlling fetal lung liquid secretion was examined in experiments in which the lungs of chronically catheterized fetal lambs (123-141 days gestational age) were exposed to dibutyryl cAMP (DBcAMP, 10(-4) M). The effect of DBcAMP was markedly gestation dependent, with the greatest effect observed in the most mature fetuses. In immature fetuses (less than 130 days, mean age 125 days) DBcAMP caused slowing of secretion, with maximal effect at 5 h. With increasing maturity the effect of DBcAMP was more pronounced and occurred earlier so that in mature fetuses (mean age 140 days) lung liquid absorption took place, with maximal effect at 2 h. Changes in lung liquid volume flow induced by DBcAMP could be blocked by addition of 10(-4) M amiloride to lung liquid. It is concluded that 1) DBcAMP induces a change in lung liquid secretion that, like epinephrine, is mediated via an increase in Na+ permeability of the apical membrane of the lung epithelium and 2) the rate-limiting step in the maturation of this process must lie beyond the generation of intracellular cAMP.

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