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1.
Pediatr Res ; 50(3): 365-73, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11518824

ABSTRACT

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.


Subject(s)
Animals, Newborn/physiology , Ductus Arteriosus/anatomy & histology , Etanidazole/analogs & derivatives , Nitric Oxide/antagonists & inhibitors , Papio/physiology , Prostaglandins/metabolism , Animals , Bisbenzimidazole/metabolism , Blood Pressure/drug effects , Cardiovascular Agents/pharmacology , DNA Fragmentation , Ductus Arteriosus/drug effects , Ductus Arteriosus/physiology , Endothelial Growth Factors/metabolism , Enzyme Inhibitors/pharmacology , Etanidazole/metabolism , Fetus/physiology , Fluorescent Dyes , Hydrocarbons, Fluorinated/metabolism , Hypoxia/metabolism , Immunohistochemistry , In Situ Nick-End Labeling , Indicators and Reagents/metabolism , Indomethacin/pharmacology , Lymphokines/metabolism , Nitroarginine/pharmacology , Respiratory Physiological Phenomena/drug effects , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
2.
Am J Physiol Regul Integr Comp Physiol ; 281(1): R291-301, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11404305

ABSTRACT

Permanent closure of the full-term newborn ductus arteriosus (DA) occurs only if profound hypoxia develops within the vessel wall during luminal obliteration. We used fetal and newborn baboons and lambs to determine why the immature DA fails to remodel after birth. When preterm newborns were kept in a normoxic range (Pa(O(2)): 50-90 mmHg), 86% still had a small patent DA on the sixth day after birth; in addition, the preterm DA wall was only mildly hypoxic and had only minimal remodeling. The postnatal increase in Pa(O(2)) normally induces isometric contractile responses in rings of DA; however, the excessive inhibitory effects of endogenous prostaglandins and nitric oxide, coupled with a weaker intrinsic DA tone, make the preterm DA appear to have a smaller increment in tension in response to oxygen than the DA near term. We found that oxygen concentrations, beyond the normoxic range, produce an additional increase in tension in the preterm DA that is similar to the contractile response normally seen at term. We predicted that preterm newborns, kept at a higher Pa(O(2)), would have increased DA tone and would be more likely to obliterate their lumen. We found that preterm newborns, maintained at a Pa(O(2)) >200 mmHg, had only a 14% incidence of patent DA. Even though DA constriction was due to elevated Pa(O(2)), obliteration of the lumen produced profound hypoxia of the DA wall and the same features of remodeling that were observed at term. DA wall hypoxia appears to be both necessary and sufficient to produce anatomic remodeling in preterm newborns.


Subject(s)
Ductus Arteriosus/metabolism , Ductus Arteriosus/physiology , Hypoxia/metabolism , Hypoxia/physiopathology , 6-Ketoprostaglandin F1 alpha/metabolism , Animals , Animals, Newborn , Cyclooxygenase Inhibitors/pharmacology , Dinoprostone/metabolism , Enzyme Inhibitors/pharmacology , In Vitro Techniques , Indomethacin/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Oxygen/pharmacology , Papio , Sheep
3.
Am J Respir Crit Care Med ; 160(5 Pt 1): 1481-5, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10556109

ABSTRACT

We studied the synthesis of surfactant and the effect of prenatal betamethasone treatment in vivo in very preterm baboons. Ten pregnant baboons were randomized to receive either betamethasone (beta) or saline (control) 48 and 24 h before preterm delivery. The newborn baboons were intubated, treated with surfactant, and ventilated for 6 d. They received a 24-h infusion with the stable isotope [U-(13)C]glucose as precursor for the synthesis of palmitic acid in surfactant phosphatidylcholine (PC). Palmitic acid in surfactant PC became enriched 27 +/- 2 h after the start of the isotope infusion and was maximally enriched at 100 +/- 4 h. The fractional synthesis rate of PC palmitate in the beta group (1.5 +/- 0.2%/d) was increased by 129% above control (0.7 +/- 0.1%/d) (p < 0.02, Mann- Whitney U test). The absolute synthesis rate of PC in the beta group [1.6 +/- 0.3 micromol/kg/d] was increased by 128% above controls [0.7 +/- 0.2 micromol/kg/d] (p < 0.02). These data show that the synthesis of endogenous surfactant from plasma glucose as precursor is a slow process. It is shown, for the first time in vivo, that prenatal glucocorticosteroids stimulate the synthesis of surfactant PC in the very premature baboon.


Subject(s)
Animals, Newborn/metabolism , Betamethasone/pharmacology , Glucocorticoids/pharmacology , Phosphatidylcholines/biosynthesis , Animals , Betamethasone/administration & dosage , Carbon Isotopes , Gestational Age , Glucocorticoids/administration & dosage , Glucose/metabolism , Lung/metabolism , Palmitates/metabolism , Papio , Pulmonary Surfactants
4.
Pediatr Res ; 45(1): 19-29, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9890604

ABSTRACT

Permanent closure of the ductus arteriosus requires loss of cells from the muscle media and development of neointimal mounds, composed in part of proliferating endothelial cells. We hypothesized that postnatal ductus constriction produces hypoxia of the inner vessel wall; we also hypothesized that hypoxia might lead to cell death and the production of vascular endothelial cell growth factor (VEGF), a hypoxia-inducible growth factor that stimulates endothelial proliferation. We mapped the distribution of hypoxia in newborn baboons and correlated it with the appearance of cell death (TUNEL technique), VEGF expression, and endothelial proliferation (proliferating cell nuclear antigen expression). In the full-term baboon (n=10), the ductus was functionally closed on Doppler examination by 24 h after delivery. Regions of the ductus where the lumen was most constricted were associated with moderate/intense hypoxia; VEGF expression was increased in the hypoxic muscle media, and luminal endothelial cells, adjacent to the hypoxic media, were proliferating. Cells in the most hypoxic regions of the ductus wall were undergoing DNA fragmentation. In contrast, regions of the ductus with mild degrees of hypoxia had no evidence of cell death, VEGF expression, or endothelial proliferation. Cell death and endothelial proliferation seemed to be limited to regions of the full-term ductus experiencing moderate/intense hypoxia. In the premature baboon (67% gestation) (n=24), only 29% closed their ductus by Doppler examination before d 6. None of the premature baboons, including those with a closed ductus by Doppler, had evidence of moderate/intense hypoxia; also, there was no evidence of cell death, VEGF expression, endothelial proliferation, or neointima formation by d 6. Therefore, the premature ductus is resistant to developing hypoxia, even when its lumen is constricted; this may make it susceptible to later reopening.


Subject(s)
Ductus Arteriosus, Patent/physiopathology , Hypoxia/metabolism , Animals , Animals, Newborn , Constriction, Pathologic , Ductus Arteriosus, Patent/therapy , Endothelial Growth Factors/biosynthesis , Gestational Age , In Situ Nick-End Labeling , Lymphokines/biosynthesis , Papio , Proliferating Cell Nuclear Antigen/analysis , Time Factors , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
5.
Am J Physiol ; 275(6): L1078-88, 1998 12.
Article in English | MEDLINE | ID: mdl-9843844

ABSTRACT

Surfactant protein (SP) A gene transcription is developmentally regulated and stimulated by hormones and factors that increase intracellular cAMP. The baboon (b) genome contains two highly similar SP-A genes, bSP-A1 and bSP-A2. With the use of a ribonuclease protection assay with gene-specific probes, the two bSP-A genes were found to be differentially regulated during baboon fetal lung development in that expression of the bSP-A2 gene appeared to be induced to a high level at a later time in gestation than that of the bSP-A1 gene. Both the bSP-A1 and bSP-A2 genes were found to be highly responsive to the inductive effects of cAMP in baboon fetal lung explants in culture. By DNase I footprinting and electrophoretic mobility shift assays with bacterially expressed thyroid transcription factor-1 (TTF-1) and type II cell nuclear extracts, three TTF-1 binding elements were identified within the 255-bp region flanking the 5'-end of each bSP-A gene; however, these differed in position and spacing for the two bSP-A genes. To functionally define the genomic regions that are required for cAMP regulation of bSP-A gene expression in type II cells, fusion genes composed of various amounts of 5'-flanking DNA from the bSP-A1 and bSP-A2 genes linked to the human growth hormone structural gene as a reporter were transfected into type II cells in primary culture. We found that 255 bp of 5'-flanking DNA, which contain three TTF-1 binding elements, from bSP-A1 and bSP-A2 genes were sufficient to mediate high basal and cAMP-inducible expression in type II cells. We also observed that there were no obvious differences in the magnitude of the responses of these fusion genes to cAMP treatment.


Subject(s)
DNA/genetics , DNA/physiology , Gene Expression Regulation/physiology , Proteolipids/genetics , Pulmonary Surfactants/genetics , Animals , Base Sequence/genetics , Binding Sites/physiology , Bucladesine/pharmacology , Culture Techniques , Fetus/cytology , Fetus/physiology , Genome , Humans , Lung/cytology , Lung/embryology , Molecular Sequence Data , Nuclear Proteins/metabolism , Papio/embryology , Promoter Regions, Genetic/genetics , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , RNA, Messenger/metabolism , Structure-Activity Relationship , Thyroid Nuclear Factor 1 , Transcription Factors/metabolism
6.
Am J Respir Crit Care Med ; 158(6): 1982-9, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9847296

ABSTRACT

We evaluated surfactant metabolism and function and the effects of antenatal glucocorticoids in very preterm baboons. Pregnant baboons were randomized to receive saline (controls) or 6 mg betamethasone (beta) 48 and 24 h before delivery at 125 +/- 2 d gestation (term is 184 d). The newborn baboons were treated with [14C]dipalmitoylphosphatidylcholine-labeled surfactant and ventilated for 6 d. Lung function for six control and six betamethasone-treated animals was similar. Recoveries of 14C-saturated phosphatidylcholine (Sat PC) were similar: 4.8% (control) and 3.6% (beta) in alveolar wash and 15.4% (control) and 17.7% (beta) in total lungs. Alveolar and total lung pool sizes of Sat PC were about 23 and 190 micromol/kg, respectively. The preterm baboons secreted 8.7% (control) and 6.5% (beta) of de novo synthesized Sat PC labeled with 3H-palmitate from Day 5 to Day 6. These preterm baboons had high estimated Sat PC synthetic and net tissue accumulation rates but low secretion of Sat PC. The large aggregate surfactant fractions from the preterm baboons had high minimal surface tensions and were less effective when used to treat surfactant-deficient preterm rabbits than surfactant from newborn or adult baboons. Ventilation of the preterm baboon was associated with surfactant functional and metabolic abnormalities that were not altered by antenatal glucocorticoids.


Subject(s)
Pulmonary Surfactants/metabolism , Respiration, Artificial , 1,2-Dipalmitoylphosphatidylcholine/administration & dosage , 1,2-Dipalmitoylphosphatidylcholine/metabolism , 1,2-Dipalmitoylphosphatidylcholine/therapeutic use , Animals , Animals, Newborn , Betamethasone/administration & dosage , Betamethasone/therapeutic use , Bronchoalveolar Lavage Fluid/chemistry , Carbon Radioisotopes , Disease Models, Animal , Female , Fetus/drug effects , Gestational Age , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Lung/metabolism , Maternal-Fetal Exchange , Palmitic Acid/metabolism , Papio , Placebos , Pregnancy , Pulmonary Alveoli/metabolism , Pulmonary Surfactants/administration & dosage , Pulmonary Surfactants/physiology , Pulmonary Surfactants/therapeutic use , Rabbits , Radiopharmaceuticals , Random Allocation , Surface Tension , Tritium
7.
Am J Physiol ; 274(4): R1169-76, 1998 04.
Article in English | MEDLINE | ID: mdl-9575985

ABSTRACT

Abnormalities of premature newborn adaptation after preterm birth result in significant perinatal mortality and morbidity. We assessed the effects of short-term (24 h) fetal betamethasone exposure on preterm newborn baboon pulmonary and cardiovascular regulation and renal sodium handling during the first 24 h after birth. Male fetal baboons (Papio) (124-day gestation, term 185 days) received ultrasound-guided intramuscular injections of saline (n = 5) or betamethasone (0.5 mg/kg; n = 5). Fetuses were cesarean delivered 24 h later, treated with 100 mg/kg surfactant, and ventilated by adjusting peak inspiratory pressures to maintain PCO2 values of 35-50 mmHg for 24 h. Betamethasone- vs. saline-treated mean +/- SE newborn body weights (0.45 +/- 0.02 vs. 0.41 +/- 0.01 kg) were similar. Although prenatal betamethasone did not affect postnatal lung function (PCO2, arterial/alveolar O2 gradient, or dynamic compliance), plasma hormone (cortisol or thyroxine), or catecholamine levels, mean arterial pressure (25 +/- 1 vs. 32 +/- 1 mmHg), plasma sodium concentration (132 +/- 2 vs. 138 +/- 1 meq/l), glomerular filtration rate (0.07 +/- 0.02 vs. 0.16 +/- 0.02 ml.min-1.kg-1), and renal total sodium reabsorption (1.5 +/- 0.5 vs. 16.0 +/- 3.0 mu eq.min-1.kg-1) values were significantly lower in saline-treated than in betamethasone-treated newborns at 24 h. We conclude that despite the fact that there are no pulmonary and endocrine effects, antenatal glucocorticoid exposure alters premature newborn baboon vascular and renal glomerular function and improves sodium reabsorption after preterm delivery.


Subject(s)
Adaptation, Physiological , Animals, Newborn/physiology , Betamethasone/pharmacology , Glucocorticoids/pharmacology , Prenatal Exposure Delayed Effects , Animals , Blood Pressure/drug effects , Catecholamines/blood , Electrolytes/blood , Endocrine Glands/drug effects , Endocrine Glands/physiology , Female , Gestational Age , Kidney/drug effects , Kidney/physiology , Lung/drug effects , Lung/physiology , Male , Papio , Pregnancy
8.
Crit Care Med ; 25(9): 1560-4, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9295832

ABSTRACT

OBJECTIVE: To study, in a model of prolonged mechanical ventilation, the role of continuous bed rotation on lung function and pathology. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Healthy adult baboons (Papio cynocephalus), anesthetized with ketamine, sedated, paralyzed, mechanically ventilated for 11 days, and monitored with pulmonary and peripheral arterial catheters. INTERVENTIONS: Animals were divided into two experimental groups: a) mechanical ventilation alone (control, n = 7); and b) mechanical ventilation with continuous bed rotation therapy to 45 degrees (continuous rotation group, n = 5). Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 12 mL/ kg. Bronchoalveolar lavage was performed through a fiberoptic bronchoscope. Nursing care procedures, antacids, enteral feeding, and prophylactic antibiotics were administered. MEASUREMENTS AND MAIN RESULTS: Measurements of hemodynamics, pulmonary functions, lung volumes, arterial blood gases, and chest radiographs were done daily. Bronchoalveolar lavage was performed at days 0, 7, and 11. There were no significant changes in hemodynamics, gas exchange, or pulmonary functions during the study period in either group. Microbiological surveillance cultures were negative in both experimental groups. In the control group after 7 days, six of seven animals developed patchy atelectasis; by day 11, two of seven animals demonstrated persistent radiologic abnormalities. Bronchoalveolar lavage neutrophils were significantly increased in control animals at days 7 and 11. Lung pathology in the control group showed areas of bronchiolitis, with surrounding bronchopneumonia in five of seven animals. None of the continuous rotation animals showed any radiologic or morphologic abnormalities. CONCLUSIONS: Prolonged mechanical ventilation in the control group resulted in atelectasis, increased concentrations of bronchoalveolar lavage neutrophils, and mild pneumonitis. These effects were not associated with changes in lung volumes, oxygenation, or hemodynamic parameters. Continuous bed rotation helped to prevent these abnormalities.


Subject(s)
Beds/standards , Lung Diseases/etiology , Lung Diseases/prevention & control , Respiration, Artificial/adverse effects , Rotation , Animals , Blood Gas Analysis , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Lung Diseases/diagnosis , Lung Volume Measurements , Male , Papio , Respiration, Artificial/methods , Tidal Volume , Time Factors
9.
Am J Physiol ; 271(4 Pt 1): L609-16, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8897909

ABSTRACT

In the present study, we found that surfactant protein A (SP-A) mRNA levels, which are barely detectable in baboon fetal lung at midgestation (92 days), are increased approximately four fold between 125 and 140 days gestation, approximately 7-fold between 140 and 160 days, and approximately 1.5-fold between 160 and 174 days gestation. We also investigated the effects of dibutyryl-adenosine 3',5'-cyclic monophosphate (DB-cAMP) and dexamethasone (Dex) on SP-A gene expression in lung explants from fetal baboons at 92, 125, 140, 160, and 174 days of gestation (term = 184 days). SP-A mRNA levels, which were barely detectable in lung tissues from 92- and 125-day fetal baboons before culture, were induced after incubation for 5 days in serum-free medium and were markedly stimulated by DBcAMP. Dex caused a dose-dependent inhibition of SP-A mRNA levels and antagonized the stimulatory effect of DBcAMP. SP-A mRNA was detectable in lung tissues from 140-day fetal baboons before culture; the levels were further induced after culture and were increased greatly by DBcAMP. Again, Dex antagonized the induction of SP-A mRNA by DBcAMP. The stimulatory effects of DBcAMP and inhibitory effects of Dex on SP-A mRNA levels in lung tissues of 92- to 140-day gestational age fetal baboons were highly similar to those observed in studies using lung explants of midgestation human abortuses. By contrast, SP-A mRNA was present in relatively high levels in lung tissues of 160- and 174-day fetal baboons before culture and was relatively unaffected after incubation for 5 days in control medium. In lung explants from 160- and 174-day fetal baboons, the stimulatory effect of DBcAMP and inhibitory effect of Dex on SP-A mRNA levels were relatively modest compared with the effects of these agents on SP-A mRNA in fetal lung tissues from 92-, 125-, and 140-day gestational age fetuses. These findings suggest that, with increased lung maturation and the developmental induction of SP-A gene expression, there is a decrease in responsiveness of the fetal lung to the stimulatory effects of cAMP and inhibitory effects of glucocorticoids on SP-A gene expression.


Subject(s)
Proteolipids/genetics , Pulmonary Surfactants/genetics , Animals , Bucladesine/pharmacology , Dexamethasone/pharmacology , Electrophoresis, Gel, Two-Dimensional , Female , Gene Expression Regulation, Developmental , Gestational Age , Glucocorticoids/pharmacology , Lung/embryology , Male , Organ Culture Techniques , Papio , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , RNA, Messenger/genetics
10.
Am J Physiol ; 271(4 Pt 1): L617-30, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8897910

ABSTRACT

The gene encoding surfactant protein A (SP-A) is expressed in type II pneumonocytes and is developmentally and hormonally regulated in fetal lung tissue. SP-A is encoded by a single-copy gene in rabbits, dogs, rats, and mice. By contrast, the human genome contains two similar genes, hSP-A1 and hSP-A2, which are differentially regulated during development and differentially regulated by adenosine 3',5'-cyclic monophosphate (cAMP) and glucocorticoid treatment of human fetal lung in culture. In the present study, we have isolated and characterized baboon genomic clones containing two highly similar SP-A genes. Restriction mapping of these clones, together with Southern analysis of genomic DNA, indicates that these comprise two distinct baboon SP-A genes. Sequence comparison of DNA upstream of the transcription initiation sites and within the 3'-untranslated regions encoded by exon VI indicates that one of the baboon SP-A genes (bSP-A1) is more similar to hSP-A1, whereas the other (bSP-A2) is more similar to hSP-A2. Primer extension analysis of baboon lung mRNA indicates that both baboon SP-A genes utilize conserved transcription initiation sites. Reverse transcriptase-polymerase chain reaction analysis of RNA isolated from lung tissues of fetal baboons of 160 days gestational age indicates that both bSP-A1 and bSP-A2 are expressed in baboon fetal lung and that mRNA transcripts of bSP-A1 and bSP-A2 genes are primarily comprised of sequences encoded by exons I and III-VI. However, minor transcripts of the bSP-A1 gene containing exon II and exon II plus an extension also were detected. The presence of two SP-A genes in the baboon suggests that duplication of the SP-A gene occurred > 26.5 million years ago, before divergence of the baboon lineage from the man-gorilla-chimpanzee clade.


Subject(s)
Papio/genetics , Proteolipids/genetics , Pulmonary Surfactants/genetics , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , Exons , Genes , Humans , Molecular Sequence Data , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , RNA, Messenger/genetics , Rabbits , Restriction Mapping , Sequence Alignment , Sequence Homology, Amino Acid
11.
Am J Respir Crit Care Med ; 152(1): 113-20, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7599809

ABSTRACT

Preterm rabbits from 14 litters were delivered at 27 d gestation, anesthetized, and treated with surfactant at birth, 15 min, or 30 min after the onset of mechanical ventilation. Doses of surfactant ranging from 0 to 100 mg/kg body weight were given intratracheally and the rabbits were ventilated for 45 min after birth. Pressure-volume curves and dynamic compliances demonstrated that the dose response to surfactant progressively decreased with delayed treatment. Following surfactant treatments of 50 mg/kg at birth, 15 min, and 30 min, peak lung volumes at 35 cm H2O were increased by 49, 30, and 8.4%, respectively over those of untreated controls. Lung lavages from rabbits receiving surfactant at 30 min had significantly higher protein contents and minimum surface tensions on the Wilhelmy balance than those from rabbits treated at birth (23.1 +/- 1.1 versus 16.0 +/- 2.7 dynes/cm), and lung sections from rabbits treated at 30 min had a significantly less uniform distribution of surfactant than those from rabbits treated at birth. While increasing phospholipid concentrations may reverse the inhibition of surfactant by serum proteins in vitro, there was a progressive inability of exogenous surfactant to overcome this inhibition in vivo following delayed administration to very immature rabbits. This inability to overcome inhibition with increasing surfactant dose was associated with a less uniform distribution of surfactant following its delayed administration.


Subject(s)
Biological Products , Pulmonary Surfactants/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome, Newborn/therapy , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Humans , Infant, Newborn , Lung Volume Measurements , Pulmonary Surfactants/therapeutic use , Rabbits , Surface Tension , Time Factors
12.
Am J Respir Crit Care Med ; 151(6): 1989-97, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7767549

ABSTRACT

Pathophysiologic and biochemical (surfactant protein and phospholipid) features were studied in a baboon model of hyperoxia-induced bronchopulmonary dysplasia (BPD) and superimposed infection. A total of 20 baboons were delivered by hysterotomy at 76% of gestation (140 d of gestational age) and were randomized into four groups, consisting of two control and two injury groups. Animals constituting a group that was managed on a pro re nata (PRN) basis were ventilated with clinically appropriate oxygen for the 16-d experimental period and served as ventilatory controls. They underwent an initial period of 42 h during which they demonstrated evidence of hyaline membrane disease (HMD), but began recovery at 42 h and by Day 6 appeared to have maximally recovered. At the time of these animals' killing, concentrations of surfactant proteins, messenger ribonucleic acids (mRNAs), and phospholipids were similar to those of normal adult baboons. Gestational control animals were delivered and killed without ventilation at 156 d gestational age. Surfactant protein-A (SP-A) and phospholipid concentrations in these animals' lavage fluids were about 10% of those in the PRN animals. Animals with BPD were subjected to positive-pressure ventilation and an FIO2 of 1.0 for 11 d, followed by 5 d of an FIO2 sufficient to maintain PaO2 at 40 to 50 mm Hg. The animals with BPD and infection were treated in the same way as the BPD group, except that 10(8) Escherichia coli were instilled intratracheally on Day 11, concomitantly with the reduction in FIO2.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bronchopulmonary Dysplasia/metabolism , Escherichia coli Infections/metabolism , Glycoproteins/metabolism , Proteolipids/metabolism , Pulmonary Surfactants/metabolism , Animals , Blotting, Northern , Bronchoalveolar Lavage Fluid/chemistry , Bronchopulmonary Dysplasia/microbiology , Bronchopulmonary Dysplasia/physiopathology , Female , Humans , Infant, Newborn , Male , Papio , Phospholipids/metabolism , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , Pulmonary Surfactants/deficiency , RNA, Messenger/analysis
13.
Am J Respir Crit Care Med ; 151(3 Pt 1): 854-66, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7881683

ABSTRACT

The surfactant protein secretory cells in airway and alveolar epithelium were studied in premature baboons with bronchopulmonary dysplasia and superimposed infection. PRN animals were delivered by hysterotomy at 140 d gestational age and ventilated on clinically appropriate oxygen for a 16-d experimental period. To assess 0 time and sacrifice time gestational parameters, 140 and 156 d were studied. BPD animals were delivered at 140 d and ventilated with positive-pressure ventilation and an FIO2 of 1.0 for 11 d followed by 5 d of oxygen sufficient to maintain PAO2 at 40 to 50 mm Hg. BPD-infected animals were comparably ventilated and treated like the BPD group except that 10(8) E. coli organisms were endotracheally instilled on Day 11. In situ hybridization studies for mRNA expression of SP-A, SP-B, and SP-C revealed that an SP-A mRNA deficiency, present at 140 d, persisted in the BPD and BPD-infected groups, whereas SP-A mRNA was abundant in PRN and 156 d gestation control groups. SP-B and SP-C mRNA expression in the two hyperoxically injured groups was particularly extensive in cells around peribronchiolar and perivasicular sites. Immunostaining with SP-A, SP-B, and SP-C antibodies showed variable staining patterns. The study clearly demonstrates that a deficiency of SP-A mRNA expression persists in chronic lung injury and that variable protein staining patterns are manifested depending upon the underlying pathology.


Subject(s)
Bronchopulmonary Dysplasia/metabolism , Escherichia coli Infections/metabolism , Glycoproteins/biosynthesis , Proteolipids/biosynthesis , Pulmonary Surfactants/biosynthesis , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/genetics , Bronchopulmonary Dysplasia/microbiology , Gene Expression/physiology , Glycoproteins/genetics , Humans , Immunohistochemistry , In Situ Hybridization , Infant, Newborn , Lung/metabolism , Lung/ultrastructure , Microscopy, Electron , Papio , Positive-Pressure Respiration , Proteolipids/genetics , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/ultrastructure , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , Pulmonary Surfactants/deficiency , Pulmonary Surfactants/genetics , RNA, Messenger/genetics
14.
Am J Obstet Gynecol ; 166(5): 1551-9, 1992 May.
Article in English | MEDLINE | ID: mdl-1595812

ABSTRACT

OBJECTIVE: The effects of antenatal hormones on postnatal surfactant mobilization were evaluated in preterm rabbits. STUDY DESIGN: Pregnant rabbits were treated with vehicle, betamethasone, or thyrotropin-releasing hormone for 2 days before cesarean section at 29 days' gestation (term 31 days). Newborns were mechanically ventilated or allowed to spontaneously breathe, and groups were compared by analysis of variance. RESULTS: Neither antenatal corticosteroids nor thyrotropin-releasing hormone increased radiolabeled precursor incorporation, alveolar wash or total lung saturated phosphatidylcholine pools, lung clearance of radiolabeled rabbit surfactant, or estimated net secretion of saturated phosphatidylcholine. However, saturated phosphatidylcholine pools in alveolar wash increased 2.7-fold during the first 24 hours in spontaneously breathing rabbits versus 2.1-fold in mechanically ventilated thyrotropin-releasing hormone-treated and control rabbits (p less than 0.05). In addition, estimated net secretion of precursor-derived saturated phosphatidylcholine was 50% higher after 24 hours in spontaneously breathing rabbits. CONCLUSION: Mechanical ventilation may have hindered the mobilization of surfactant saturated phosphatidylcholine pools to the alveolar space after birth in preterm rabbits, but maternal hormonal therapies did not appear to influence this adaptive process or change surfactant metabolism.


Subject(s)
Adrenal Cortex Hormones/pharmacology , Gestational Age , Lung/embryology , Pulmonary Surfactants/metabolism , Respiration, Artificial , Thyrotropin-Releasing Hormone/pharmacology , Adrenal Cortex Hormones/administration & dosage , Animals , Betamethasone/pharmacology , Female , Lung/drug effects , Lung/metabolism , Maternal-Fetal Exchange , Phosphatidylcholines/metabolism , Pregnancy , Pulmonary Alveoli/metabolism , Rabbits , Thyrotropin-Releasing Hormone/administration & dosage
15.
Res Commun Chem Pathol Pharmacol ; 74(3): 259-72, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1663646

ABSTRACT

We studied the effects of acute smoke exposure on lung and alveolar macrophage (AM) function in New Zealand white rabbits. Six rabbits were exposed to smoke (SE, N = 6) and a control group of rabbits (SS, N = 6) were exposed to sham smoke. The smoke exposure consisted of 60 tidal volume breaths of air and smoke which were aspirated by syringe from a sampling port of a smoke chamber. The smoke was generated by the combustion of 20 ml diesel fuel and 0.2 g polycarbonate plastic shavings. The smoke was administered in 8-9 min. The rabbits were then killed and the lungs were removed for lavage. Acute smoke exposure caused a significant (p = 0.037) increase in bronchoalveolar lavage fluid levels of leukotriene B4 in the SE rabbits; 643 (+/- 30, SEM) pg/ml compared to 539 (+/- 43, SEM) pg/ml for SS rabbits at 3-4 min post-exposure. Lung surfactant, measured as mumoles/kg phosphatidylcholine, was decreased (p = 0.039) in SE rabbits' bronchoalveolar lavage fluid, 1.07 (+/- 0.12, SEM) -vs- 1.45 (+/- 0.15, SEM) for SS. Furthermore, cultured SE alveolar macrophage superoxide secretion after stimulation with phorbol myristate acetate was significantly decreased versus SS alveolar macrophage superoxide values at 40 min in culture. We conclude that acute smoke exposure causes immediate increases in bronchoalveolar lavage fluid levels of LTB4, and decreases in alveolar macrophage superoxide production and lung surfactant. These changes in chemical mediators may contribute to the lung injury caused by the smoke insult.


Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Leukotriene B4/analysis , Macrophages, Alveolar/metabolism , Phosphatidylcholines/analysis , Smoke/adverse effects , Superoxides/metabolism , Animals , Epoprostenol/analogs & derivatives , Epoprostenol/pharmacology , Leukocyte Count , Rabbits
16.
J Appl Physiol (1985) ; 68(3): 1134-41, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2341338

ABSTRACT

Pregnant rabbits received bethamethasone (0.05, 0.2, 0.4, or 0.5 mg.kg-1.day-1) or vehicle control for 2 days before delivery of fetuses at 27 days gestation to evaluate dose-related effects on surfactant pool sizes with and without ventilation, pressure-volume measurements, lung protein leaks, and precursor incorporation into lung saturated phosphatidylcholine (PC). Alveolar wash-saturated PC pool sizes in betamethasone-exposed fetuses were less than in controls (P less than 0.01). At higher doses, total lung saturated PC also decreased (P less than 0.01). Maximal lung volumes on pressure-volume loops were larger than controls only at the 0.4 mg.kg-1.day-1 dose (P less than 0.05). The larger maximal volumes, despite decreased saturated PC pools, indicated increased responsiveness of the steroid-treated lungs to the smaller saturated PC pool sizes. Vascular-to-alveolar iodinated albumin leak decreased with steroid treatment independently of dose (P less than 0.01). No consistent pattern of increased precursor incorporation into saturated PC by lung slices was seen. Our results indicate that, in preterm rabbits exposed to a range of maternal corticosteroid doses, the beneficial lung maturational effect of structural alterations with increased responses to endogenous saturated PC pools was maximal even at the lowest dose.


Subject(s)
Betamethasone/administration & dosage , Fetal Organ Maturity/drug effects , Lung/drug effects , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Female , Fetal Organ Maturity/physiology , Lung/embryology , Lung/physiology , Maternal-Fetal Exchange , Phosphatidylcholines/metabolism , Pregnancy , Proteins/metabolism , Rabbits
17.
Exp Lung Res ; 16(2): 131-43, 1990.
Article in English | MEDLINE | ID: mdl-2328711

ABSTRACT

The responses of the adult rabbit lung to multiple doses of surfactant after intratracheal injections of either natural calf surfactant or Surfactant-TA were evaluated. For each surfactant, four groups of 1.4-kg rabbits were studied: group 1 received 100 mg of surfactant containing isotopically-labeled dipalmitoylphosphatidylcholine; group 2 received the same labeled surfactant and then three tracheal injections of vehicle; group 3 received labeled surfactant and then three doses (100 mg) of unlabeled surfactant; group 4 was treated in the same way as group 3 except that the final dose was of the labeled surfactant. All rabbits were killed, and alveolar washes were recovered 24 h after the labeled surfactant dose had been given. The amount of labeled palmitate-saturated phosphatidylcholine (Sat PC) in alveolar washes did not change after multiple doses of calf surfactant, indicating that subsequent doses did not alter the clearance of previous doses. The four doses of calf surfactant increased the alveolar Sat PC pool size by a factor of 2.5 only when measured 6 h after the last dose, but the total lung Sat PC pool size doubled, indicating a loss of most of the surfactant Sat PC to the lung tissue. In contrast, Surfactant-TA increased the alveolar pool size by a factor of 4 after the single dose and by a factor of 11 after the multiple doses, and the percentage clearance of labeled Sat PC from the lungs decreased with multiple doses, indicating an effect of subsequent doses on the initial dose. The quantity of Sat PC cleared from the lungs increased by about a factor of 2 after the multiple doses of Surfactant-TA. Although repetitive surfactant doses changed alveolar and lung Sat PC pool sizes the quantity of Sat PC cleared from the lungs increased, and the lungs accommodated the large amount of surfactant without short-term adverse effects.


Subject(s)
Lung/drug effects , Pulmonary Surfactants/pharmacology , Animals , Bronchoalveolar Lavage Fluid/metabolism , Cattle , Choline , Female , Lung/cytology , Lung/metabolism , Palmitic Acid , Palmitic Acids , Phosphatidylcholines/metabolism , Rabbits , Surface-Active Agents/pharmacology
18.
J Appl Physiol (1985) ; 67(1): 429-37, 1989 Jul.
Article in English | MEDLINE | ID: mdl-2759972

ABSTRACT

Preterm lambs were delivered at 132 days gestational age, treated with 100 mg/kg radiolabeled natural sheep surfactant or Surfactant TA, and ventilated for times up to 24 h. Compared with an untreated group that developed respiratory failure by 5 h, both surfactant-treated groups had stable respiratory function to 24 h. Although only approximately 13% of the labeled surfactant phosphatidylcholine was recovered by alveolar wash at 24 h, there was no significant loss of the labeled phosphatidylcholine from the lungs. Labeled palmitic acid intravascularly injected at 1 h of age comparably labeled lung phosphatidylcholine in the three groups of lambs at 5 h; however, only approximately 0.5% of the labeled phosphatidylcholine was secreted to the air spaces of surfactant-treated lambs at 24 h. Labeled lysophosphatidylcholine given with the natural sheep surfactant was taken up by the lungs, converted to phosphatidylcholine with 30-40% efficiency, and resecreted to the air spaces, demonstrating recycling of a phospholipid. The large surfactant aggregates recovered from alveolar washes by centrifugation were surface active and contained approximately 76% of the air-space phosphatidylcholine in both surfactant-treated groups. Although clinical status was comparable, alveolar washes and surfactant subfractions from Surfactant TA-treated lambs had better surface properties than did sheep surfactant-treated lambs. These studies identified no detrimental effects of surfactant treatments on endogenous surfactant metabolism and indicated that the surfactants used for treatments were recycled by the preterm ventilated lamb lung.


Subject(s)
Animals, Newborn/metabolism , Lysophosphatidylcholines/administration & dosage , Phosphatidylcholines/metabolism , Pulmonary Surfactants/metabolism , Sheep/metabolism , Animals , Female , Male
19.
Pediatr Res ; 25(4): 423-8, 1989 Apr.
Article in English | MEDLINE | ID: mdl-2726320

ABSTRACT

Premature rabbits delivered by cesarean section at 28 d of gestation were each given intratracheally 75 mg/kg of radiolabeled preparation of either natural rabbit surfactant, natural calf surfactant, or surfactant-TA. Each newborn rabbit was ventilated for up to 6 h in a ventilator-plethysmograph with individual adjustments of peak inspiratory pressures to attain tidal vol of 12-15 mL/kg body wt. Dynamic compliances were about 0.7-0.9 mL/cm H2O. kg after treatment with the three surfactants and did not deteriorate during the 6-h study. Rabbits were randomly studied at 0.5, 1.5, 3, 4.5, and 6 h of age for the recovery of the labeled surfactant phosphatidylcholine in the total lungs (alveolar wash plus postlavage lung tissue). The labeled phosphatidylcholine was cleared from the total lungs of rabbits treated with natural rabbit or calf surfactants at comparable rates of about 25%/6 h. In contrast, the clearance rate of surfactant-TA phosphatidylcholine from the total lungs was not significantly different from 0. Lipids from rabbit surfactant that had been administered intratracheally were only minimally present in the blood and liver. In other similarly treated rabbits, the lipids from radiolabeled rabbit surfactant and liposomes of dipalmitoylphosphatidylcholine that had been injected intravenously were recovered in blood and liver in substantial quantities. These studies documented significant losses of rabbit and calf surfactant phosphatidylcholine but not surfactant-TA phosphatidylcholine from the lungs of preterm ventilated rabbits. The losses were not explained by surfactant losses to the vascular compartment.


Subject(s)
Animals, Newborn/metabolism , Lung/metabolism , Phosphatidylcholines/pharmacokinetics , Pulmonary Surfactants/pharmacokinetics , Respiration, Artificial , Animals , Bronchoalveolar Lavage Fluid/analysis , Liver/analysis , Rabbits , Random Allocation
20.
Eur Respir J Suppl ; 3: 16s-20s, 1989 Mar.
Article in English | MEDLINE | ID: mdl-2500940

ABSTRACT

We tested whether maternal administration of corticosteroids, thyrotropin-releasing hormone (TRH), triiodothyronine (T3) or their combinations, would improve lung function of ventilated preterm newborn rabbits. Maternal corticosteroids and T3 treatments did not improve lung compliance; TRH did. The major effect observed was a large improvement in lung compliance following maternal treatment with corticosteroids plus TRH in animals treated with surfactant. These agents made the lung "receptive" to the surfactant treatment. T3 did not improve lung function and no augmented response to surfactant was seen. None of the treated groups had surfactant pool sizes significantly different from controls. The mechanisms of action of corticosteroids and/or TRH seemed to be independent of changes in surfactant pool sizes.


Subject(s)
Adrenal Cortex Hormones/pharmacology , Bronchoalveolar Lavage Fluid/analysis , Lung/drug effects , Maternal-Fetal Exchange , Pulmonary Surfactants/pharmacology , Thyrotropin-Releasing Hormone/pharmacology , Triiodothyronine/pharmacology , Animals , Female , Humans , Infant, Newborn , Lung Compliance/drug effects , Lung Injury , Pregnancy , Pulmonary Surfactants/analysis , Rabbits , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome, Newborn/prevention & control
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