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Biomedical subjects

B A Holm

Publications and source records attributed to B A Holm.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dysfunction of guinea-pig pulmonary surfactant and type II pneumocytes after repetitive challenge with aerosolized ovalbumin.

BACKGROUND: Asthma symptoms may partially be caused by a surfactant dysfunction. The inflammatory reaction, so characteristic of asthma, involves a protein invasion of airways which harmfully affects the surfactant function. However, mild asthma attacks might also impede the surfactant synthesis in alveolar type II cells. OBJECTIVE: The present study evaluates the hypothesis that type II pneumocyte metabolic function might be disturbed in a model of mild asthma. METHODS: Immunized, as well as not immunized control guinea-pigs, were challenged three times at two-day intervals with 0.04% ovalbumin aerosol. Bronchoalveolar lavage (BAL) was performed one day after the last challenge and the fluid was evaluated for surface activity, and content of phospholipids and proteins. Alveolar type II cells were isolated and their ability to incorporate a 3H labeled surfactant precursor was evaluated. RESULTS: BAL fluid from immunized and challenged animals showed less surface activity (P < 0.01) when compared with BAL fluid from controls, not immunized but challenged. Most likely the reduced surface activity was caused by a 74% increase in the protein concentration (P < 0.05). Isolated type II cells from immunized and challenged animals had 33% less phospholipids than cells from controls (P < 0.05), and phosphatidylcholine synthesis was reduced 35% (P < 0.05). CONCLUSION: These results suggest that the synthesis, intra-cellular storage, and biophysical activity of surfactant are decreased in an intermittent and mild form of asthma.

Allergens↗
PubMed1997

Physiology and pathophysiology of lung development.

Over the past few years, there has been a considerable improvement in our understanding of the normal development of the fetal lung and its regulation. These advances have occurred mostly through increased knowledge of molecular biological mechanisms of growth and differentiation. These advances have also resulted in an improvement in our comprehension of the pathological basis of various pulmonary diseases. As a result of this new and improved knowledge, new and innovative therapeutic modalities are being introduced into clinical practice. The introduction of surfactant therapy into the clinical setting was one such milestone in neonatal respiratory management. Pulmonary surfactant is responsible for stabilising alveoli during normal respiration, thereby preventing atelectasis or alveolar flooding. Disease processes which result in an insufficiency in surfactant, such as respiratory distress syndrome (RDS) or congenital diaphragmatic hernia (CDH), generally carry a very high mortality rate. Exogenous surfactant administration reduces both the mortality and morbidity associated with RDS and its sequelae, and its efficacy in the treatment of CDH is now being evaluated clinically. Moreover, laboratory studies suggest that surfactant therapy may be used in combination with other treatments, such as tracheal occlusion to promote lung growth in CDH, in order to achieve a maximal effect in these complex, multifactorial lung diseases.

Journal Article↗
PubMed1997

Contributions by individual lungs to the surfactant status in congenital diaphragmatic hernia.

Laboratory evidence has recently confirmed clinical reports suggesting that the surfactant system is abnormal in congenital diaphragmatic hernia (CDH). Autopsy series show that, although both lungs are affected by the maldevelopment, the ipsilateral lung is more severely affected. The aim of this study was to examine the surfactant status in each lung in a lamb model of CDH. The lamb CDH model was created on the left side at 80 d of gestation and delivered near term. Subsequently, the lungs were removed and separated from each other. Bronchoalveolar lavage and type II pneumocyte isolations were performed on each side separately. Lavage analyses showed decreased phospholipid (0.12 versus 0.42 mg/g), per cent phosphatidylcholine (51% versus 79%) surfactant-associated protein A (0.20 versus 2.68 mg/g), and surfactant-associated protein-B (0.35 versus 2.21 mg/g) in CDH lungs compared with control lungs. However, no differences were seen between the ipsilateral and contralateral lungs of either CDH or control groups. This was in contrast to the phosphatidylcholine biosynthetic abilities of type II cells isolated from CDH lungs, which were not only lower than those from control lungs (0.15 versus 0.40 nmol/10(6) cells/h), but were also significantly worse in the ipsilateral CDH lung compared with the contralateral CDH lung (0.10 versus 0.20 nmol/10(6) cells/h). Further studies utilizing radiolabeled exogenous surfactant injected in the lower contralateral lung indicate that discrepancies between the presence of type II cell function differences between lungs, and the lack of biochemical differences between the two lungs in CDH, may be due to in utero mixing of lung fluid.

Animals↗
PubMed1996

Surfactant rescue in the fetal lamb model of congenital diaphragmatic hernia.

Surfactant therapy given before the onset of ventilation (surfactant prophylaxis) has been shown to improve oxygenation, ventilation, and pulmonary hemodynamics in the lamb model of congenital diaphragmatic hernia (CDH). The aim of this study was to assess the efficacy of surfactant administered after the onset of ventilation ("surfactant rescue"). Ten lambs with surgically created CDH were instrumented, at full term, to measure pulmonary blood flow and pulmonary vascular resistance (PVR). Catheters also were positioned for monitoring of systemic blood pressure and arterial blood gases. The animals were delivered and pressure-ventilated according to a standard protocol (PIP, 30 cm; PEEP, 4 cm; respiratory rate, 60 breaths per minute). After 30 minutes of ventilation, five animals received an intratracheal dose of calf lung surfactant extract (50 mg/kg). The animals were studied for 4 hours. Surfactant rescue had no discernible effect on Pco2, Pco2, or pH. There was an increase in pulmonary blood flow, but it was not significant. The dramatic improvement in oxygenation, ventilation, and pulmonary blood flow found with prophylactic surfactant cannot be reproduced when surfactant is administered as rescue therapy. This indicates that the surfactant is not being delivered adequately, the lungs have already incurred significant barotrauma, and/or the surfactant is being inactivated by alveolar protein. Therefore, the authors suggest that when exogenous surfactant therapy is being considered for the fetus or newborn with CDH, it should be administered as early as possible, preferably before the infant's first breath. Prenatal diagnosis and delivery in a tertiary care center would facilitate this optimum management.

Animals↗
PubMed1996

Can cardiac weight predict lung weight in patients with congenital diaphragmatic hernia?

Left ventricular disproportion (decreased left-to-right ventricular internal diameter ratio) has been correlated with fetal or neonatal survival in cases of congenital diaphragmatic hernia (CDH). Because cardiac development is intimately related to lung development in the normally developing fetus, the authors sought to determine whether cardiac weight correlates with lung weight in control and CDH lambs at term. Twenty lambs had CDH created surgically at 80 days' gestation and were sacrificed at term for measurement of lung and heart weight. Nine unoperated lambs served as controls. Analysis of the relationship between heart weight and lung weight was performed for both groups, and regression curves were generated as mean +/- 2 standard deviations (SD) for each group of lambs. All data are expressed in grams. For CDH lambs, the relationship between heart and lung weight is as follows: lung weight = 0.69 x heart weight + 37 g. For control lambs, the equation is: lung weight = -0.004 x heart weight + 135 g. There is no overlap of these regression curves at 2 SD of the mean. The curves differ significantly, and the P value exceeds .05. The results suggest that cardiac weight can be used to predict lung weight in CDH and control lambs at term. The authors speculate that this difference in weight is attributable to underdevelopment of the left ventricle in CDH. Given that left ventricular disproportion has been described as early as the pseudoglandular stage of lung development in human fetuses with CDH, it is hoped that echocardiographic parameters can be used to differentiate the fetuses with adequate lung volume from those whose lung volume is incompatible with extrauterine life. Patients in the latter group may benefit from surgical correction of the diaphragmatic defect in utero.

Analysis of Variance↗
PubMed1996

Surfactant decreases pulmonary vascular resistance and increases pulmonary blood flow in the fetal lamb model of congenital diaphragmatic hernia.

INTRODUCTION: Experiments using animal models of neonatal respiratory distress syndrome have shown a decrease in pulmonary vascular resistance (PVR) with surfactant replacement, whereas studies with the lamb model of congenital diaphragmatic hernia (CDH) have demonstrated improvement in oxygenation and lung mechanics with this therapy. The aim of the present study was to measure the effects of surfactant replacement therapy on the pulmonary hemodynamics of the lamb model of CDH. METHODS: Ten lambs with surgically created CDH and five control lambs were instrumented at term, with the placental circulation intact. Ultrasonic flow probes were positioned around the main pulmonary artery and the common origin of the left and right pulmonary arteries to record total lung and main pulmonary artery blood flow. Catheters were inserted to record systemic, pulmonary, and left atrial pressure. Five CDH animals received 50 mg/kg of surfactant by tracheal instillation just before delivery. All 15 animals were then ventilated for 4 hours. RESULTS: Correcting the surfactant deficiency in the CDH lamb resulted in a significant increase in pulmonary blood flow, a decrease in PVR, and a reduction in right-to-left shunting. These improvements in hemodynamics were associated with a significant improvement in gas exchange over 4 hours. CONCLUSION: The fetal lamb model of CDH has elevated PVR in comparison to controls. Prophylactic surfactant therapy reduces this resistance and dramatically increases pulmonary blood flow while reducing extrapulmonary shunt. A surfactant deficiency may be partially responsible for the persistent pulmonary hypertension in neonates with CDH.

Animals↗
PubMed1996

Perfluorocarbon-associated gas exchange improves oxygenation, lung mechanics, and survival in a model of adult respiratory distress syndrome.

OBJECTIVE: To compare the effectiveness of perfluorocarbon-associated gas exchange to volume controlled positive pressure breathing in supporting gas exchange, lung mechanics, and survival in an acute lung injury model. DESIGN: A prospective, randomized study. SETTING: A university medical school laboratory approved for animal research. SUBJECTS: Neonatal piglets. INTERVENTIONS: Eighteen piglets were randomized to receive perfluorcarbon-associated gas exchange with perflubron (n=10) or volume controlled continuous positive pressure breathing (n=8) after acute lung injury was induced by oleic acid infusion (0.15 mL/kg iv). MEASUREMENTS AND MAIN RESULTS: Arterial and venous blood gases, hemodynamics, and lung mechanics were measured every 15 mins during a 3-hr study period. All animals developed a metabolic and a respiratory acidosis during the infusion of oleic acid. Following randomization, the volume controlled positive pressure breathing group developed a profound acidosis (p<.05), while pH did not change in the perfluorocarbon-associated gas exchange group. Within 15 mins of initiating perfluorocarbon-associated gas exchange, oxygenation increased from a PaO2 of 52 +/- 12 torr (6.92 +/- 1.60 kPa) to 151 +/- 93 torr (20.0 +/- 12.4 kPa) and continued to improve throughout the study (p<.05). Animals that received volume controlled positive pressure breathing remained hypoxic with no appreciable change in PaO2. Although both groups developed hypercarbia during oleic acid infusion, PaCO2, steadily increased over time in the control group (p<.01). Static lung compliance significantly increased postrandomization (60 mins) in the animals supported by perflurocarbon-associated gas exchange (p<.05), whereas it remained unchanged over time in the volume controlled positive pressure breathing group. However, survival was significantly higher in the perfluorocarbon-associated gas exchange group with eight (80%) of ten animals surviving the entire study period. Only two (25%) of the eight animals in the volume controlled positive pressure breathing group were alive at the end of the study period (log-rank statistic, p=.013). CONCLUSIONS: Perflurocarbon-associated gas exchange enhanced gas exchange, pulmonary mechanics, and survival in this model of acute lung injury.

Animals↗
PubMed1996

Partial liquid ventilation enhances surfactant phospholipid production.

OBJECTIVE: To study the effect of partial liquid ventilation on phospholipid metabolism. DESIGN: Prospective, controlled laboratory study. SETTING: University-affiliated animal research facility. SUBJECTS: Mature New Zealand white rabbits (n = 17). INTERVENTIONS: The rabbits were sedated, anesthetized, and instrumented with tracheostomy and the insertion of an arterial catheter. The rabbits were sequentially assigned to receive conventional mechanical ventilation or partial liquid ventilation with Perflubron (18 mL/kg by bolus fill). Ventilator strategies were identical in both groups and consisted of an FiO2 of 0.5, positive end-expiratory pressure of 4 cm H2O, effective tidal volume of 8 to 13 mL/kg, and rate to maintain Pco2 of 30 to 40 torr (4.0 to 5.3 kPa). Phosphatidylcholine was labeled in vivo by injection of 3H-methylcholine (25 microCi/kg iv). Ventilation was continued for 5.5 hrs. MEASUREMENTS AND MAIN RESULTS: When animals were killed, phosphatidylcholine was extracted from the total lung lavage and from the pulmonary parenchyma. After the separation of phospholipids by thin-layer chromatography, the 3H activity was determined by liquid scintillation counting. Inorganic phosphorus was also determined to assess the enrichment of the phosphatidylcholine. The 3H-phosphatidylcholine activity in the partial liquid ventilation treated- vs. control rabbits demonstrated a 53% increase (p = .051) in the lavage and a 48% increase (p = .013) in the parenchyma for a net 50% (p = .012) total pulmonary increase. The phospholipid content of the partial liquid ventilation treated- vs. the control rabbits demonstrated a 78% increase (p = .046). CONCLUSIONS: We conclude that partial liquid ventilation with Perflubron appears to have no negative impact on phospholipid metabolism but rather enhances surfactant phospholipid synthesis and secretion.

Acute Disease↗
PubMed1996

Quantitation of the alveolar distribution of surfactant mixtures in normal and injured lungs.

The uptake and distribution of two surfactant mixtures, Exosurf and Infasurf, instilled into the lungs of normal and hyperoxia-exposed (100% O2, 60 h) rabbits, were quantified at the alveolar level using flow cytometry and fluorescence microscopy. The surfactants were labeled with the fluorescent phospholipid analog NBD-C12-PC (1-palmitoyl-2-[12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-glycero-3-phosphocholine ) in 100:1 molar ratio. Rabbits were killed 2 h after the instillation of either surfactant (80 mg phospholipid [PL]/kg), and alveolar macrophages (AM) and alveolar type II (ATII) cells were isolated and examined for the presence of NBD fluorescence. The fractions of cells, with NBD fluorescence values higher than autofluorescence, isolated from the lungs of air-breathing rabbits instilled with either Infasurf or Exosurf, were 84% and 63% for AM, and 55% and 45% for ATII cells. Exposure of rabbits to hyperoxia decreased the fraction of NBD-positive AM following Infasurf instillation, and the mean increase in NBD-associated fluorescence in ATII cells following Exosurf instillation. Our results suggest that sublethal hyperoxia decreases the short-term uptake but not the distribution of intratracheally instilled Exosurf.

Animals↗
PubMed1996

Content of dipalmitoyl phosphatidylcholine in lung surfactant: ramifications for surface activity.

The content of dipalmitoyl phophatidylcholine (DPPC) in the phosphatidylcholine (PC) fraction of calf lung surfactant extract (CLSE) is measured by gas chromatography (GC) and estimated from the widely used osmium tetroxide assay for disaturated phosphatidylcholine (DSPC). The surface-active properties of model phospholipid/apoprotein surfactants with varying DPPC content are also defined and compared relative to CLSE. GC analysis of fatty acids in PC isolated from CLSE indicated a possible range of 30 to 65% for DPPC content depending on C16:0 fatty chain mismatching, and further studies using phospholipase A2 treatment indicated an actual DPPC content < or = 41%. The osmium tetroxide assay gave a very high value of 70% for the DSPC content of surfactant PC, and experiments with synthetic phospholipids demonstrated that this assay responded inappropriately in the presence of monounsaturated PC, leading to falsely elevated DSPC values. The influence of DPPC content on adsorption and film behavior was investigated in model surfactants containing 40, 60, and 80% DPPC (DPPC/egg PC/egg PG, 40:50:10, 60:30:10, and 80:10:10 by mol) combined with 1.3% hydrophobic surfactant protein (SP)-B and -C. The biophysical properties of the model surfactant with 40% DPPC were found to be closer to CLSE than those of mixtures with 60 or 80% DPPC. The adsorption of dispersions containing 40% DPPC with 1.3% SP-B, C was almost identical to CLSE and was improved in rate and magnitude compared with the mixtures with higher DPPC content (60 or 80%). In Wilhelmy balance studies of cycled films, respreading was increased and maximum surface pressure was decreased for the 40% versus higher DPPC content mixtures, again approaching CLSE in behavior. All synthetic phospholipid (SPL):SP mixtures lowered surface tension to < 1 mN/m in oscillating bubble studies at physiologic cycling rate (20 cpm), but the 40% DPPC mixture had a time dependent most closely matching that of CLSE. Our measured DPPC content near 40% for lung surfactant PC, and the similarly high activity of a related synthetic phospholipid/apoprotein model mixture, suggest that exogenous surfactants with relatively low DPPC contents might be important for future study and development.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1996

Congenital diaphragmatic hernia. A historical review.

Congenital diaphragmatic hernia (CDH) has been described, studied, and treated for over 400 years. A historical perspective is given. Great strides have been made in the care of patients with CDH; however, the mortality rate remains 30% to 60%. Consideration of historical references, observations, and achievements in the study of CDH is important for the continued advancement and improvement in our understanding of and future success in treating infants and children with CDH.

Hernia, Diaphragmatic↗
PubMed1996

Prenatal diagnosis of congenital diaphragmatic hernia with predictors of mortality.

Since the late 1970s, congenital diaphragmatic hernia (CDH) has been diagnosed antenatally by ultrasound. With improvements in ultrasound resolution, CDH is being diagnosed more frequently and at an earlier stage in gestation. This provides an opportunity to administer in utero therapy to the fetus. As 50% of babies born with CDH survive, it is imperative that accurate prognostic indicators are available to guide antenatal therapy. Antenatal diagnosis and prognostic indicators are discussed.

Hernia, Diaphragmatic↗
PubMed1996

Pulmonary parenchymal abnormalities in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia results in abnormal lung development. There is a global hypoplasia with both lungs affected, the ipsilateral lung more severely. This results in a reduction in the number of bronchial divisions and a decrease in the quantity and maturity of the alveoli. The pneumocytes are dysfunctional, resulting in a total quantitative and qualitative reduction in surfactant and a decrease in antioxidant enzyme activity.

Hernias, Diaphragmatic, Congenital↗
PubMed1996

Pulmonary vascular abnormalities in congenital diaphragmatic hernia.

Persistent pulmonary hypertension poses a significant problem to the surgeon managing an infant with congenital diaphragmatic hernia. It is likely that a number of abnormalities contribute to this pathophysiologic entity. These include: (1) in the hypoplastic lung the overall cross-sectional area of the pulmonary vascular bed is reduced, (2) the muscular arteries are hypertrophied and extend more peripherally than normal, (3) the pulmonary vessels are more labile than normal and are overly sensitive to the normal stimuli of vasoconstriction, and (4) the immature surfactant-deficient lung is predisposed to barotrauma and atelectasis, resulting in alveolar hypoxemia which contributes to pulmonary hypertension. All of these interfere with the ability of the lung to accept the increase in pulmonary blood flow required by the transitional circulation. If this impairment reaches a level such that the lung cannot accept the right ventricular output then pulmonary hypertension will ensue and a poor outcome can be anticipated.

Hernia, Diaphragmatic↗
PubMed1996

Animal models in congenital diaphragmatic hernia.

The first animal model of congenital diaphragmatic hernia (CDH) was described in 1967. This was a late-gestational, surgically-created lamb model. Since then, animal modeling has become more sophisticated. Using a variety of techniques and laboratory species, animal models have been produced to investigate the pathophysiology of CDH, from whole animal physiology studies to lung molecular changes. To provide the animal tissue required, three different approaches have been used: (1) a surgically-created model which has been reported in lambs and rabbits, (2) a teratogen-induced model which to date has been described in rats and mice, and (3) a congenital model which is present in a specific pig herd. All animal models are discussed in this article.

Animals↗
PubMed1995

Pathophysiology of congenital diaphragmatic hernia. XII: Amniotic fluid lecithin/sphingomyelin ratio and phosphatidylglycerol concentrations do not predict surfactant status in congenital diaphragmatic hernia.

Abnormal development of the lung in congenital diaphragmatic hernia (CDH) results in a dysfunctional surfactant system. In premature newborns at risk for respiratory distress syndrome, amniotic fluid lecithin/sphingomyelin (L/S) ratios and phosphatidylglycerol (PG) status have been successfully used to predict the surfactant status in the fetus. The objective of this study was to assess the accuracy of L/S ratios and PG in predicting the surfactant status in CDH. The surgically created lamb CDH model was used. Animals were delivered at 140 days' gestation (term 145) and immediately killed. Before delivery amniotic fluid was collected and L/S ratios and PG status were measured. Bronchoalveolar lavage (BAL) was performed and analyzed for total phospholipid and percent phosphatidylcholine (PC). Analysis of the BAL showed that the CDH lungs had both significantly less total phospholipid (CDH 0.10 +/- 0.03 mg/g versus control (CON) 0.76 +/- 0.28 mg/g) and PC (CDH 38 +/- 7.3% versus CON 70 +/- 3.4%) when compared with controls. In contrast the L/S ratios (CDH 2.44 +/- 0.26 versus CON 2.01 +/- 0.32) and PG status (CDH 8.75 +/- 1.01 nmol versus CON 10.2 +/- 0.9) were the same in CDH and control animals. The BAL from the CDH lamb model has a significant surfactant deficiency. Amniotic fluid L/S ratios and PG status were, however, not different between the control and CDH lambs. These results indicate that amniotic fluid L/S ratios and PG do not accurately predict the surfactant status of a fetus with CDH.

Amniotic Fluid↗
PubMed1995

Pathophysiology of congenital diaphragmatic hernia. VIII: Inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia.

The pathophysiology of the lamb model of congenital diaphragmatic hernia (CDH) involves pulmonary hypoplasia, pulmonary hypertension, and surfactant deficiency. Inhaled nitric oxide (NO) is a highly selective pulmonary vasodilator. The aim of this study was to determine the effects of inhaled NO on pulmonary gas exchange, acid-base balance, and pulmonary pressures in a lamb model of CDH with or without exogenous surfactant therapy. At the gestational age of 78 days (full term, 145 days) 11 lamb fetuses had a diaphragmatic hernia created via a left thoracotomy and then were allowed to continue development in utero. After cesarean section, performed at term, six lambs received exogenous surfactant therapy (50 mg/kg, Infasurf) and five served as controls. All animals were pressure-ventilated for 30 minutes and then received 80 ppm of inhaled NO at an F1O2 of .9 for a 10-minute interval. Compared with the control lambs, the lambs with exogenous surfactant therapy had higher pH (7.17 +/- .06 v 6.96 +/- .07; P < .05), lower PCO2 (73 +/- 8 v 122 +/- 20, p < .05), and higher PO2 (153 +/- 38 v 50 +/- 23; P < .05). In control CDH lambs (without surfactant), inhaled NO did not improve pH, PCO2, or PO2, or decrease pulmonary artery pressure. In CDH lambs given exogenous surfactant, NO decreased pulmonary artery pressures (42 +/- 4 v 53 +/- 5; P < .005) and further improved PCO2 and PO2. NO also made the difference between pulmonary and systemic artery pressures more negative in the surfactant-treated lambs (-15 +/- 4 v -2.3 +/- 2.4; P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗