The surfactant protein A (SP-A) gene was disrupted by homologous recombination in embryonic stem cells that were used to generate homozygous SP-A-deficient mice. SP-A mRNA and protein were not detectable in the lungs
ABSTRACT. At birth, pulmonary vascular resistance decreases dramatically, allowing pulmonary blood flow to increase and oxygen exchange to occur in the lungs. To determine the extent to which ventilation of the fetus's lungs, oxygenation of the lungs, and umbilical cord occlusion can account for this decrease in resistance, we studied 16 chronically instrumented, near-term sheep fetuses in uteuo. We performed the experiment in a sequential fashion: we first studied the effects of ventilation alone (without oxygenation) on pulmonary vascular resistance and blood flow, and then determined the additive effects of oxygenation and cord occlusion. We calculated pulmonary vascular resistance from measurements of vascular pressures and measurements of pulmonary blood flow obtained by injecting radionuclide-labeled microspheres. We found that ventilation alone caused a large but variable increase in pulmonary blood flow, to 401% of control, no change in pulmonary arterial pressure, and a doubling of left atrial pressure. Thus, pulmonary vascular resistance fell dramatically, to 34% of control. Oxygenation caused a modest further increase in pulmonary blood flow and a decrease in mean pulmonary arterial pressure, so resistance fell to 10% of control. Umbilical cord occlusion caused no further changes in pressure, flow, or resistance. Unexpectedly, the fetuses' pulmonary blood flow responses to ventilation fell into two groups: the mean increase was maximal in eight of the 16 fetuses but was only 20% of the cumulative increase in the other eight. We found no differences between the two groups of fetuses to explain their different responses. We conclude that ventilation and oxygenation together can account for the decrease in pulmonary vascular resistance to levels that occur at birth. Moreover, ventilation alone can account for most of this decrease. In the circulation of both fetuses and newborns, the main role of the right ventricle is to deliver blood to the gas exchange circulation for uptake of oxygen and removal of carbon dioxide. In the fetus this delivery is achieved by virtue of the pulmonary vascular resistance being very high. Right ventricular output is thus diverted away from the lungs and toward the placenta, through the ductus arteriosus (1)(2)(3)(4) lungs become the organ of gas exchange, pulmonary vascular resistance must fall dramatically, allowing pulmonary blood flow to increase and oxygen exchange to occur in the lungs. If pulmonary vascular resistance does not fall, the syndrome of persistent pulmonary hypertension of the newborn occurs, often leading to death.Which of the many events that occur at birth are responsible for the normal decrease in pulmonary vascular resistance is not fully understood. Three major events of the birth process that could be responsible are ventilation, or rhythmic gaseous distension, of fetal lungs, oxygenation of the lungs, and occlusion of the umbilical cord. Two of these events-ventilation and oxygenation-have been studied in acutely exteriorized fetal sheep. Rhythmic ...
Pulmonary function was assessed in newborn wild-type and homozygous and heterozygous surfactant protein B (SP-B)-deficient mice after birth. SP-B+/+ and SP-B+/− mice became well oxygenated and survived postnatally. Although lung compliance was decreased slightly in the SP-B+/− mice, lung volumes and compliances were decreased markedly in homozygous SP-B−/− mice. They died rapidly after birth, failing to inflate their lungs or oxygenate. SP-B proprotein was absent in the SP-B−/− mice and was reduced in the SP-B+/− mice, as assessed by Western analysis. Surfactant protein A, surfactant proprotein C, surfactant protein D, and surfactant phospholipid content in lungs from SP-B+/− and SP-B−/− mice were not altered. Lung saturated phosphatidylcholine and precursor incorporation into saturated phosphatidylcholine were not influenced by SP-B genotype. Intratracheal administration of perfluorocarbon resulted in lung expansion, oxygenation, and prolonged survival of SP-B−/− mice and in reduced lung compliance in SP-B+/+ and SP-B+/− mice. Lack of SP-B caused respiratory failure at birth, and decreased SP-B protein was associated with reduced lung compliance. These findings demonstrate the critical role of SP-B in perinatal adaptation to air breathing.
Genetic ablation of the murine SP-B gene in transgenic mice caused lethal perinatal respiratory distress in homozygous offspring, whereas heterozygous SP-B (+/-) mice survived postnatally. In adult SP-B(+/-) mice, surfactant protein B mRNA and the alveolar lavage SP-B protein were reduced by 50% compared with wild-type littermates, consistent with the inactivation of a single SP-B allele. Expression of SP-A, SP-C, and SP-D proteins was not affected in SP-B(+/-) mice. Heterozygous SP-B(+/-) mice reached maturity in numbers expected by Mendelian inheritance of a recessive gene. Lung morphology and both intracellular and extracellular phospholipid pool size and composition were unaltered in the SP-B(+/-) mice. Despite normal survival, pulmonary function studies demonstrated a consistent decrease in lung compliance in SP-B(+/-) mice. Abnormalities of inflation/deflation curves demonstrated airway collapse at low deflation pressures. Residual volumes were increased in the SP-B(+/-) mice. In summary, SP-B mRNA and SP-B protein were reduced by 50% in SP-B(+/-) mice, resulting in abnormalities of lung compliance and air trapping, suggesting a potential susceptibility to pulmonary dysfunction associated with SP-B deficiency.
A majority of previous studies of fetal responses to acute hypoxemia has focused on the response of the sheep fetus greater than 120 days of gestation when many regulatory systems have been established. To assess the response of younger, less well-developed fetuses, we exposed two groups of fetal sheep (I, 84-91 days; II, 97-99 days gestational age) to acute hypoxemia by giving the ewe a gas mixture containing 9% O2 to breathe. We decreased descending aortic PO2 in both groups of fetuses [I, 24 +/- 6 to 14 +/- 3 (SD) Torr; II, 23 +/- 3 to 12 +/- 4 Torr] by a degree similar to that achieved in previous studies of fetuses greater than 120 days of gestation. Mean arterial blood pressure (I, 31 +/- 6; II, 40 +/- 3 Torr) did not change significantly from control values, and heart rate (I, 224 +/- 27; II, 203 +/- 16 beats/min) increased significantly in group II fetuses with hypoxemia. In group I and II fetuses, as in older fetuses, cerebral, myocardial, and adrenal blood flows, measured by the microsphere technique, increased, and pulmonary blood flow decreased. These responses mature early and are likely local vascular responses to decreases in oxygen content. Combined ventricular output and umbilical-placental blood flow decreased significantly in both groups. Unlike the response of the fetus greater than 120 days, acute hypoxemia did not decrease blood flow to the musculoskeletal and cutaneous circulations (group I only), gastrointestinal, or renal circulations.(ABSTRACT TRUNCATED AT 250 WORDS)
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