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Biomedical subjects

R A Rhoades

Publications and source records attributed to R A Rhoades.

At least 55 records · Page 3Linked to original sources
PubMed1987

Immunomodulation of local and systemic immunity after subchronic pulmonary exposure of mice to benzo(a)pyrene.

A single intratracheal (i.t.) instillation of 3H-BaP (2.5 mg/kg) cleared rapidly from the lung with a half life of approximately 8 h. In contrast, the amount of 3H-BaP (expressed as counts/min/mg tissue) in the lung-associated lymph nodes (LALN) continued to increase over a 6 day period while a low, persistent level of BaP was detected in the spleen. To determine whether humoral immunity was affected by BaP accumulation in lymphoid organs, B6C3F1 mice were given seven daily i.t. instillations of 0.4, 4.0 or 40 mg BaP/kg, and immunized with sheep red blood cells (SRBC) 1 day after the last BaP instillation. When antigen was given by i.t. instillation, the number of antigen-specific, antibody-forming cells (AFC) decreased in the LALN after BaP exposure. Interestingly, the number of AFC in the LALN from BaP-exposed mice were significantly increased after intraperitoneal (i.p.) immunization. However, these same mice had lower numbers of AFC in the spleen. When 51Cr-SRBC were instilled in the lung, the pulmonary clearance of radiolabeled antigen was slowed in BaP-exposed mice. When 51Cr-SRBC were placed in the peritoneal cavity, the amount of radiolabeled antigen that reached the LALN was similar in BaP-exposed and vehicle mice. However, four times more radiolabeled antigen translocated from the peritoneal cavity to the lung in BaP-exposed mice, while significantly less antigen reached the spleen and liver. Thus, BaP-induced immunomodulation of the humoral immune response appears to be influenced by the route of immunization, as well as by the proximity of the responding lymphoid tissue to the site of BaP deposition.

Animals↗
PubMed1987

Cyclooxygenase metabolites contribute to oleic acid-induced lung edema by a pressure effect.

We investigated the role that lung-derived arachidonic acid metabolites play in the acute changes in pulmonary hemodynamics, airway function, and lung fluid balance following oleic acid-induced injury in the isolated blood free perfused lung. A bolus injection of oleic acid (OA) emulsion (12 mg) into the pulmonary artery caused a rapid increase in pulmonary arterial pressure, inspiratory pressure, and weight gain. These pathophysiologic changes were not due to emboli per se, but were correlated with release of the vaso- and broncho-constrictive prostanoids, thromboxane A2 (measured as thromboxane B2) and prostaglandin F2 alpha. The leukotrienes (C4, D4, and E4) and prostacyclin (measured as 6 keto-prostaglandin F1 alpha) were not released by OA injury. Ibuprofen, a cyclooxygenase inhibitor, blocked the release of the vasoconstrictive prostanoids and also attenuated the rise in pressures and the development of edema indicating an important functional role for the prostanoids in the fluid imbalance. Ibuprofen also attenuated the increase in bronchoalveolar lavage protein but the protein leak was not completely prevented, suggesting that OA-induced increases in protein permeability occurred independently of prostanoid or leukotriene action. These data indicate that OA-induced edema formation was greatly amplified by arachidonic acid mediated pressure increases.

Animals↗
PubMed1986

Fatty acid synthesis in the fetal lung: relationship to surfactant lipids.

The aims of this study were to investigate the control of fatty acid synthesis and its relationship to surfactant production in the fetal lung during alteration of hormonal and substrate conditions. Lung explants from 18 day fetuses (term = 22 days) which were cultured 2 days in the presence of 10 mM lactate showed parallel acceleration of de novo fatty acid synthesis (3H2O incorporation) and [14C]choline incorporation into disaturated phosphatidylcholine (DSPC) compared to culture of explants in glucose. Both the cultured and fresh explants were resistant to the classical short term (4 h) cAMP inhibition of fatty acid synthesis with 3 mM dibutyryl cAMP or 0.5 mM aminophylline. In the cultured explants short term cAMP elevation increased DSPC production, and long term (2 day) cAMP elevation caused a further increase in DSPC synthesis and also stimulated fatty acid synthesis. In cultured explants from 17 day fetuses, dexamethasone (0.1 microM) caused a synergistic increase with aminophylline in both fatty acid synthesis and DSPC production whereas, in explants from 18 day fetuses, dexamethasone inhibited both processes and reduced the level of stimulation of DSPC and fatty acid synthesis seen with aminophylline alone. Dexamethasone also reduced the stimulation of both DSPC and fatty acid synthesis produced in the culture of 18 day explants with bacitracin (0.5 mg/ml), whereas the combination of bacitracin and aminophylline resulted in a synergistic increase in DSPC production. Culture with glucagon (0.1 microM) also stimulated DSPC synthesis but at physiological levels insulin had no effect on either DSPC or fatty acid synthesis. These data show that lung fatty acid synthesis exhibits unique features of fatty acid synthesis regulation compared to other lipogenic tissues and also suggest a link between de novo fatty acid synthesis and surfactant production during the critical period of accelerated lung maturation.

Aminophylline↗
PubMed1986

Role of histamine in acute oleic acid-induced lung injury.

The action of histamine in oleic acid (OA)-induced injury was investigated using the isolated guinea pig lung perfused with blood-free media. OA infusion caused a significant increase in pulmonary arterial pressure, airway inspiratory pressure, lung weight, and protein flux across the alveolar-capillary barrier. These changes were dose dependent and caused injury regardless of the chemical form of OA (salt or free acid). Triolein (a neutral fat) infused at comparable emulsion particle size did not alter lung weight or bronchoalveolar lavage protein concentration in the perfused lung, suggesting that mechanical obstruction or emboli per se is not responsible for initiating early events in OA-induced injury. Infusion of OA caused a significant early histamine release into the venous effluent in the presence of aminoguanidine, a histamine catabolism inhibitor. Pretreatment with H1-receptor antagonists significantly attenuated OA-induced increase in lung weight and protein leak. These data support the link between OA-induced mast cell degranulation, histamine release, and OA-induced edema.

Animals↗
PubMed1986

Histamine action in paraquat-induced lung injury.

We investigated direct histamine release and its effects in edema formation following paraquat (PQ) injury in a blood-free, perfused rat lung preparation. Under control conditions, perfusate histamine levels from the lung averaged 9.5 +/- 1.4 ng/ml. Lungs perfused with paraquat (1 mM) showed marked increases in pulmonary arterial pressure (133%), airway pressure (74%), alveolarcapillary protein flux (200%), and lung weight (38%). Prior to any detectable lung weight or pressure changes, PQ caused a 300% increase in perfusate histamine. Diphenhydramine (1.0 X 10(-5) M), a specific H1-histamine receptor antagonist, blocked the increased protein flux that followed PQ administration and significantly delayed edema. Furthermore, diphenhydramine attenuated the rise in PGF2 alpha. Conversely, histamine release was partially attenuated by the cyclooxygenase inhibitor, ibuprofen, at 2.4 X 10(-5) M, the same level that we had previously shown to block an early rise in PGF2 alpha and the onset of edema after PQ. These data show that the increased alveolar-capillary protein flux that occurred with PQ injury was attenuated by an H1-receptor antagonist and suggest that histamine is a primary mediator in paraquat-induced injury and that histamine subsequently stimulates prostaglandin release.

Animals↗
PubMed1986

Integrated substrate utilization by perinatal lung.

The aims of this study were to examine the pattern and relative utilization of exogenously supplied substrates by the perinatal rat lung and to study their functional relationship at a key period of lung maturation (3 days before birth until one day after birth). Maximal incorporation of 14C-labeled substrates (glucose, lactate, glycerol, and beta-hydroxybutyrate) from the media into lung lipids occurred one day before birth and corresponded to maximal incorporation of 14C-choline into disaturated phosphatidylcholine (DSPC) (63 n moles X hr-1 X g-1), and to maximal increase in tissue DSPC concentration. Whereas, 14C-palmitate utilization for phospholipid synthesis was refractory to changes in DSPC synthesis. Lactate was shown to be a key substrate in fetal lung. When lactate and glucose were supplied at physiological concentrations, lactate: 1) provided 60% of the carbons for de novo fatty acid synthesis compared to only 9% from glucose, 2) produced 5 times more CO2 than glucose (23.9 vs. 4.9 u moles CO2 X hr-1 X g-1) and 3) altered the major fate of glucose incorporated into lung lipid from the fatty acid moiety to the glycerol moiety. Glycerol and palmitate were relatively unimportant energy fuels in the perinatal lung.

3-Hydroxybutyric Acid↗
PubMed1984

Isolated perfused lung preparation for studying altered gaseous environments.

The isolated perfused lung (IPL) preparation is ideally suited to investigate lung dynamics and cellular function, and is easily adapted to investigating biochemical and physiological responses to environmental insults. The IPL offers several advantages which permit one to study endothelial/epithelial interactions that are often disrupted with other model systems (e.g., isolated cells, minces, slices, homogenates, etc.). The IPL developed in our laboratory was devised for the rat lung and allows four lungs to be perfused simultaneously in which control over ventilation, flow, pressure, pH, PO2 and PCO2 can be maintained. Isolated lungs perfused for 1 to 2 hr at a flow rate of 10 mL/min exhibit less that 2% weight gain, maintain normal ATP levels, and exhibit linear substrate uptake. Mechanisms leading to changes in vascular and airway resistance, lipid metabolism, vasoactive hormones, blood gases and changes in vascular permeability mediated by environmental insults can be quantified in the IPL preparation.

Adenosine Diphosphate↗
PubMed1983

Selective action of prostaglandin F2 alpha during paraquat-induced pulmonary edema in the perfused lung.

Lung prostaglandins (PGs) play a key role in normal pulmonary vascular regulation. We investigated PG metabolism during edema formation following paraquat-induced damage with an isolated perfused rat lung preparation. Lungs perfused with paraquat (PQ), 1 X 10(-7) M to 1 X 10(-2) M, showed significant increases in PGF2 alpha prior to detectable functional and pathological changes (increases in airway resistance, vascular resistance, and edema). No changes in PGE were observed. PGF2 alpha in perfused lungs showed a dose-related response following PQ exposure (up to 300% increase over control values). Lungs perfused with PQ and ventilated with high oxygen (95% O2-5% CO2) instead of air-5% CO2 showed a dramatic potentiation in the selective increase of PGF2 alpha, with levels reaching over 1 ng/ml (a 2600% increase over control values). The addition of exogenous PGF2 alpha to the perfusate without PQ initiated edema in a dose-related fashion, indicating the potential of PGF2 alpha as a causative agent in lung edema formation from PQ injury. The addition of ibuprofen (a nonsteroidal anti-inflammatory agent) to the perfusion medium blocked endogenous release of PGF2 alpha in lungs linked to oxidant-induced edema. These data show that in the perfused lung: (1) PQ caused a selective increase of PGF2 alpha; (2) this selective increase occurred prior to the onset of edema; (3) exogenous PGF2 alpha alone induced pulmonary edema; and (4) ibuprofen, in doses which blocked PGF2 alpha, also prevented edema formation.

Animals↗
PubMed1982

Lung phosphatidate phosphatase: activity during altered physiologic states.

Phosphatidic acid phosphatase (PAPase) which catalyzes the conversion of phosphatidic acid to 1,2-diacyl-sn-glycerol was studied in fetal, neonatal, and adult rat lung microsomal fractions from whole lung under normal and altered physiological states. The maximal activity was obtained at pH 7.0 with 1.0 mM phosphatidic acid as the substrate. Twenty-one-day-old fetal rat lung averaged 20.3 +/- 0.6 SE nmol/min/mg microsomal protein compared to 9.9 +/- l.0 nmol/min/mg in liver. Following birth there was a dramatic 53% increase in the PAPase activity. Twenty-one-day-old fetal rat lungs from diabetic mothers (streptozotocin-induced) and from mothers fasted the last four days of gestation did not show altered PAPase activity. Premature breathing for 3-6 hr on day 21 of gestation also did not affect the PAPase activity. These data demonstrate that the microsomal PAPase activity (l) increases dramatically only after birth (2) is not responsive to altered physiologic state (maternal diabetes, maternal fasting, and premature breathing) and (3) may not be an important regulatory enzyme in lung surfactant phospholipid production.

Animals↗
PubMed1981

De novo fatty acid synthesis in the perfused rat lung. Incorporation of palmitate into phospholipids.

1. The incorporation of exogenously derived [14C]palmitate and endogenously synthesized [3H]palmitate (from 3H2O) was measured in the isolated perfused lung. 2. Over 40% of the fatty acid esterified into lung disaturated phosphatidylcholine was derived from de novo synthesis. 3. A major portion of the palmitate synthesized de novo was incorporated in the 2 position of disaturated phosphatidylcholine. 4. Streptozotocin-induced diabetes and the compound 5-(tetradecyloxy)-2-furoic acid markedly inhibited de novo fatty acid synthesis while the incorporation of exogenously supplied palmitate increased into disaturated phosphatidylcholine, primarily in the 2 position. 5. Treatment with insulin resulted in an increase in [14C]glucose incorporation into lung phospholipid, with the largest increase appearing in the glyceride-glycerol fraction of the phosphatidylcholine species. 6. Insulin neither stimulated de novo fatty acid synthesis nor increased exogenous palmitate incorporation. 7. These data show: (1) that de novo fatty acid synthesis in the perfused rat lung is involved in the remodeling reactions in the synthesis of phosphatidylcholine, and (2) that diabetes affects the relative contribution of de novo synthesized and exogenously supplied palmitate available for the esterification of lung phospholipid.

Animals↗
PubMed1981

Fetal lung metabolism. Response to maternal fasting.

1. Fetal lung metabolic response to maternal fasting late in gestation was investigated. 2. Maternal fasting 4 days before term was associated with low fetal plasma glucose and insulin levels but increased levels of fetal plasma glucagon, glycerol, lactate and fatty acids. 3. Fetuses from fasted mothers showed a significant decrease in body weight (30%) and lung glycogen (46%), but no change in lung protein, phospholipid or total lung DNA, suggesting that lung size is affected more than maturation. 4. Fetal lung slices incubated in vitro showed that lactate oxidation to CO2 equalled that of glucose in control fetal lungs and was unaffected by maternal fasting, while glucose oxidation was depressed (23%). 5. Maternal fasting significantly decreased in vitro incorporation of [U-14C]-glucose, [U-14C]lactate and [1-14C]palmitate into lung phospholipids. 6. Fetal lungs from fasted mothers showed increased conversion of lactate to glucose, indicating gluconeogenic potential by fetal lung. 7. These studies show that plasma lactate serves as an important energy fuel and substrate for lipid synthesis for the fetal lung, and maternal fasting markedly alters fetal lung metabolism.

Animals↗
PubMed1978

Selective action of hypoxia on rat lung cyclic AMP.

The effect of three different levels of 24-h hypobaric hypoxia (630 mm Hg, 520 mm Hg, and 340 mm Hg) on rat lung cAMP and cGMP was studied. Liver was also examined to evaluate comparatively with lung. Lung cAMP concentration averaged 33.6 +/- 2.2 (SE) pmol/mg protein, and cGMP averaged 2.4 +/- 0.21 (SE) pmol/mg protein. Twenty-four-hour hypoxia resulted in a significant 40% decrease in lung cAMP at 520 and 340 mm Hg. The magnitude of change was the same for both hypoxic levels suggesting threshold dependency. In contrast, liver cAMP was not affected by the hypoxic exposure. Lung and liver cGMP were also relatively refractory to hypoxia. The decreased cAMP concentration seen in the hypoxic lung returned to normal level within 24 hours. These data show that acute hypoxia has a selective action on lung cAMP.

Animals↗
PubMed1978

Lactate metabolism in perfused rat lung.

Glucose utilization and lactate metabolism were studied in isolated rat lungs perfused with a Krebs-Henseleit bicarbonate buffer, pH 7.4, containing either [U-14C]lactate, [U-14C]glucose, or [U-14C]alanine. Glucose uptake showed an apparent Km of 4.7 mM and a Vmax of 107 mumol-g dry wt-1-h-1. Lactate production under these conditions showed a Vmax of 82.9 mumol-g dry wt-1-h-1. At high circulating lactate level (7 mM), the perfused lung showed an increased capacity to utilize [U-14C]lactate with preferential incorporation into lung lipids. At equal molar concentration (5 mM) [U-14C]lactate was preferentially incorporated over [U-14C]glucose. Addition of 5 mM lactate to the perfusion medium did not affect lactate production. Perfused lungs from fasted rats showed higher lactate production, with increased amounts of [U-14C]alanine converted to lactate by the perfused lung, indicating lactate can also be derived from noncarbohydrate sources. These data show that under aerobic conditions the perfused lung can produce and utilize lactate simultaneously, and lactate can serve as a potential substrate for lung lipids.

Animals↗
PubMed1977

Substrate metabolism in the perfused lung: response to changes in circulating glucose and palmitate levels.

The effects of circulating levels of glucose and palmitate in the isolated perfused rat lung were investigated. Rat lungs were perfused for 1.5 hr with washed bovine erythrocytes (15% hematocrit) in Krebs-Henseleit bicarbonate buffer containing 5 g% bovine serum albumin. Glucose uptake in the perfused lung varied directly with circulating glucose concentration. Lactate production was affected proportionately more by high glucose levels than by low concentrations. Pyruvate production was decreased by both low glucose and palmitate concentration in the circulating medium. Oxidation of glucose to CO2 was depressed by low glucose and by high palmitate concentrations. Glucose incorporation into lung lipids was more strongly influenced by glucose concentration than by circulating palmitate levels. These data indicate acute changes in circulating levels of glucose and palmitate alone can act to either inhibit or stimulate glycolysis, glucose oxidation, and lipid synthesis in the perfused lung.

Animals↗
PubMed1976

Perfused lung preparation for studying altered gaseous environments.

An isolated perfused lung (IPL) preparation was used to investigate the influence of acute environmental stress on lung substrate metabolism. The IPL apparatus consists of four perfusion flasks housed in a temperature-controlled Lucite box with a circulation fan. Lungs are ventilated by a positive pressure ventilation pump. The ventilation is arranged so that the lung can be ventilated with any desired gas composition with concomitant collection of expired gases. The perfusion medium is circulated at 10 ml/min with a peristaltic blood pump, and passes through a specially designed chamber to dampen pulmonary pressure and remove emboli. The perfusion medium presently used in our experiments consisted of washed bovine red blood cells resuspended to a 15% hematocrit with Krebs-Henseleit bicarbonate buffer containing 6% dialyzed Pentex bovine serum albumin. Circulating substrates include 6muM glucose and 0.4muM palmitate. The pH is adjusted to 7.4 with 0.8M Na carbonate. Lungs perfused for 1.5 hr with this apparatus maintain viability, show little edema, maintain blood gases, and show linear incorporation of labeled glucose into lung lipids. Perfused lungs made hypocapnic show a significant (p less than 0.05) rise in lactate and pyruvate, while perfused lungs made hypercapnia show a significant decrease in pyruvate with no change in lactate.

Animals↗