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Biomedical subjects

L Frank

Publications and source records attributed to L Frank.

At least 109 records · Page 6Linked to original sources
PubMed1988

Undernutrition as a major contributing factor in the pathogenesis of bronchopulmonary dysplasia.

The protean effects of undernutrition on lung defenses and repair capabilities suggest that less than adequate nutritional support is a key pathogenetic factor in the development of bronchopulmonary dysplasia (BPD). Very-low-birthweight (VLBW, less than or equal to 1,000 g) premature infants who require intensive respiratory support have a distressingly high incidence of chronic lung disease or BPD. Many VLBW infants are currently undernourished during the most acute phase of their respiratory illness. Because VLBW newborns have only meager caloric reserves (fat, glycogen), and have only marginally sufficient stores of nutrients needed for effective lung defenses and repair capacity (vitamins A and E, copper, zinc, iron, selenium, essential fatty acids, etc.), the adequacy of nutritional support provided them will almost certainly influence their ability to tolerate early stress, and it may play a critical role in their clinical outcome. Experimental studies, combined with a limited number of clinical studies, clearly demonstrate that undernutrition can interact with each of the other well-accepted etiologic factors involved in the pathogenesis of BPD. Nutritional status affects the lung's ability to resist hyperoxic damage, to replace damaged/sloughed lung cells caused by barotrauma, to promote continued lung growth, to resist infection, and to tolerate prolonged and potentially toxic stresses in general. By providing more ideal nutritional support, clinicians may be able to apply preventive treatment to influence the outcome of intensive respiratory therapy in the VLBW newborn.

Animals↗
PubMed1988

Extension of oxygen tolerance by treatment with endotoxin: means to improve its potential therapeutic safety in man.

Treatment of adult rats with low doses of bacterial lipopolysaccharide (endotoxin) consistently results in a marked protective effect against O2-induced lung damage and lethality. We report here two means to improve the therapeutic ratio of endotoxin (ratio of dose producing desired beneficial effect/dose producing undesired toxic effects), which could make it a more acceptable pharmacologic agent for possible use in patients who require prolonged hyperoxic therapy. (a) Rats made "tolerant" to the lethal/toxic effects of high doses of endotoxin (25 mg/kg) by pretreatment with very low doses of endotoxin (10 ng----10 micrograms/kg) were found to still respond to a standard protective dose of endotoxin (500 micrograms/kg) with marked resistance to O2 toxicity. (Survival in greater than 95% O2 X 72 h = 19/20 (95%), vs. 4/17 (24%) for controls.) (b) Two chemically modified native endotoxin preparations ("endotoxoids"), with approximately 100 X decreased toxic potential, were found to have retained their ability to protect adult rats from prolonged hyperoxic exposure (90%-100% survival rates). These two experimental manipulations (use of the "endotoxin tolerance" phenomenon and treatment with partially detoxified "endotoxoids") were associated with increased lung antioxidant enzyme activities during O2 exposure in the treated animals. Continued research may eventuate in the possible clinical application of a safe form of endotoxin treatment for the prevention of O2 toxicity in humans.

Animals↗
PubMed1987

Prenatal development of lung antioxidant enzymes in four species.

We examined the chronology of development of both fetal lung antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and disaturated phosphatidylcholine ("surfactant") during late gestation in four laboratory animal species: rat, rabbit, hamster, and guinea pig. An essentially similar pattern of prenatal biochemical maturation was found in all four species. The developmental changes were characterized by (1) rapid elevations in fetal lung antioxidant enzyme levels during the final 10% to 15% of gestation, and (2) an essentially parallel rapid rise in lung surfactant content during the final 10% to 15% of gestation. The increase in the lung activity of the individual antioxidant enzymes prior to birth averaged approximately 150% to 200%. Our findings suggest that late gestational changes in the principal pulmonary antioxidant defense system (like the changes in the surfactant system) represents a normal "preparation for birth," required to assure successful functioning of the neonatal lung in the relatively oxygen-rich ex utero environment.

Animals↗
PubMed1987

PO2-dexamethasone interactions in fibroblast growth and antioxidant enzyme activity.

Fetal rat lung fibroblasts were cultured in a gas phase of 20% O2, 5% CO2 (PO2 measured, 150 Torr) or 2% oxygen, 5% CO2 (PO2 measured, 25 Torr) with or without 100 nM dexamethasone (Dex). Superoxide dismutase (SOD) activity per cell increased spontaneously during 4 days of incubation at both PO2, but catalase (CAT) activity tended to fall during this time and glutathione peroxidase (GPx) activity showed no consistent trend during this interval. Cells cultured at a low PO2 had a lower protein content and SOD activity compared with air controls. Dex inhibited cell proliferation and enhanced intracellular accumulation of protein at the low PO2 but prevented the increase in protein content without affecting cell multiplication at a PO2 of 150 Torr. SOD activity per cell was enhanced by Dex at a low PO2 but reduced in 20% O2, 5% CO2. An increase in CAT and GPx activity per cell resulted on exposing fibroblasts to Dex in the presence of low PO2. These results show that Dex affects the growth and antioxidant enzyme activity of fetal lung fibroblasts, and this action of Dex can be modulated by changing the ambient PO2.

Animals↗
PubMed1987

Guinea pig lung development: antioxidant enzymes and premature survival in high O2.

Whereas guinea pigs have advanced prenatal morphological lung development, their surfactant development is not "precocious" compared with other small laboratory animals. To investigate whether maturation of the antioxidant enzyme (AOE) system coincides more closely with surfactant development or with morphological maturation, we assayed fetal guinea pig lungs at gestational days 49-69 for superoxide dismutase, catalase, and glutathione peroxidase activities. We found that elevations in pulmonary AOE occurred in parallel with increases in surfactant during the final 10-15% of gestation. Since newborn guinea pigs behave more like adult animals in their relative intolerance to hyperoxia, we explored whether prematurely delivered guinea pigs would tolerate high O2 exposure better than full-term newborns. We found that prematures have markedly improved hyperoxic tolerance compared with newborns (time at which 50% of animals died in greater than 95% O2, 6.4 days vs. 4.5 days, respectively, P less than 0.05); and (unlike newborns) premature pups are capable of mounting an elevated AOE response to hyperoxic challenge. Thus premature guinea pigs behave more like full-term newborns of other species in respect to hyperoxic tolerance, an additional precocious feature of guinea pig development.

Animals↗
PubMed1987

Thyroid hormone depresses antioxidant enzyme maturation in fetal rat lung.

The surfactant system and antioxidant enzyme system of the lung have chronologically similar developmental patterns, and the maturation of both systems is accelerated by glucocorticoid hormones. To investigate whether thyroid hormone might also stimulate the development of the antioxidant enzyme system as well as the surfactant system, we injected pregnant rats with triiodothyronine (T3) or diluent. Fetal T3 offspring demonstrated significantly elevated T3 levels, had significantly increased lung tissue disaturated phosphatidylcholine (DSPC) and total phospholipid content, yet had significantly decreased activities of three lung antioxidant enzymes (AOE) (superoxide dismutase, catalase, and glutathione peroxidase). When dexamethasone was administered in combination with T3, fetuses demonstrated increases in lung DSPC content but decreases in AOE of magnitude equivalent to or greater than that seen with T3 alone. These findings indicate that thyroid hormone affects surfactant and AOE development in opposite ways and may have potentially harmful as well as beneficial effects on different aspects of lung development.

Animals↗
PubMed1987

Oxygen toxicity in neonatal rats: the effect of endotoxin treatment on survival during and post-O2 exposure.

Neonatal rats were treated with low doses of bacterial lipopolysaccharide (endotoxin) to test for a protective effect of endotoxin against O2 toxicity and the severe inhibition of normal lung development which occurs during prolonged exposure to hyperoxia. The rationale for the prophylactic use of endotoxin included its marked protective effect against pulmonary O2 toxicity in adult rats and its lung growth-promoting effect in experimental pulmonary stress models. Neonatal rats (4-5 days old) survived a 14-day exposure to greater than 95% O2 equally well whether treated with saline (39/51 = 76%) or with endotoxin (41/51 = 80%). However, during the following 24 h of gradual weaning to room air breathing, there was a marked difference in survival between the endotoxin group (32/41 = 78%) and the saline pups (14/39 = 36%) (p less than 0.001). Both groups showed inhibition of lung development (alveolarization) during O2 exposure, but endotoxin treatment compared to saline was associated with increased specific lung volume (5.33 versus 4.50 ml/100 g) (air control = 4.08), smaller mean airspace diameter (mean linear intercept = 49.0 versus 55.8 microns) (air control = 43.3), increased specific internal surface area (4393 versus 3232 cm2/100 g) (air control = 3753), and greater preservation of alveolar wall capillary patency (24.83 versus 18.52% "capillary density") (air control = 27.70%). We conclude that endotoxin treatment resulted in significant protection against O2 toxicity in neonatal rats which was manifested during readaptation to room air breathing. The protective effect was likely due to a combination of reduced inhibition of lung growth and development and reduced hyperoxic damage to the respiratory membrane of the lung.

Animals↗
PubMed1987

Lung development in the fetal guinea pig: surfactant, morphology, and premature viability.

Guinea pigs demonstrate "precocious" physical and functional development, with newborns displaying open eyes, hair, self-feeding, and temperature regulation. In addition, morphologic lung development is precocious in the guinea pig, with advanced alveolarization taking place in utero. To explore whether pulmonary surfactant development is also advanced, and at what stage prematurely delivered guinea pigs are capable of survival, we delivered fetal guinea pigs at 2- to 3-day intervals from day 49 of gestation to day 69 (birth). These were examined for chronologic changes in lung morphology, lung tissue disaturated phosphatidylcholine, phosphatidylglycerol and glycogen content, and serum glucocorticoid and thyroid hormone levels. Other prematurely delivered guinea pigs were given brief postnatal resuscitation and their survival noted. We confirmed advanced morphologic lung maturation, yet found that surfactant development, with antecedent hormone peaks and glycogen depletion, occurs during the final 10-15% of gestation. Lung biochemical development is thus "on time" in the guinea pig, rather than "precocious" compared to other frequently studied laboratory animals. In addition, greater than 50% of fetal guinea pigs are capable of survival by 8 days prior to term, well in advance of premature survivability in other small-sized species.

Animals↗
PubMed1987

Treatment of descending thoracic aneurysm with an intraaortic occluder.

Elective treatment of descending thoracic aneurysms involves direct surgery, with Dacron graft replacement of the diseased aortic segment. When the patient's condition contraindicates major surgery, however, the surgeon should consider using an extraanatomic approach-implanting an ascending aorta-to-abdominal aorta Dacron bypass graft in a ventral position and leaving the diseased segment undisturbed. After such a procedure, the descending thoracic aorta must be excluded from the normal circulation. For this purpose, we have designed an intraaortic occluding technique in which an umbrella-like device is implanted immediately distal to the left subclavian artery. This technique has proved safe and uncomplicated in canine experiments and is ready for clinical trials.

Journal Article↗
PubMed1986

Use of anti-idiotypic antibodies to explore genetic mechanisms of production of anti-DNA antibodies.

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies with a broad range of antigenic specificities, including specificity for double-stranded DNA. Analysis of the idiotypic profile of anti-DNA antibodies both in humans and mice has demonstrated presence of cross-reactive idiotypes, suggesting that they arise from a restricted number of germline genes. Our laboratory has previously reported the generation of 3I, a monoclonal anti-idiotypic antibody which recognizes a cross-reactive idiotype on anti-DNA antibodies in a majority of unrelated humans with SLE. We have recently studied the expression of 3I in sera of three human kindreds with familial SLE. We found 6 of 8 SLE patients and 15 of 19 unaffected family members had elevated 3I reactivity. Eleven of these family members had no anti-DNA activity despite elevated 3I reactivity, suggesting that expression of this idiotype in certain individuals is part of the normal immune response. In another set of experiments using an in vitro culture system we examined somatic mutants of the S107 mouse myeloma cell line. This line makes an antibody which bears the T15 idiotype, a common idiotype on antibodies to the bacterial antigen phosphoryl choline (PC). U4, a mutant, makes an immunoglobulin which varies by one amino acid from the parent protein, retains the T15 idiotype, but loses reactivity with PC and acquires reactivity with DNA. We have found that some anti-DNA antibodies in mice with spontaneous lupus and in mice immunologically induced to make anti-DNA antibodies bear the T15 idiotype and may represent somatic mutants arising in vivo.

Animals↗
PubMed1986

New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamindes.

N-(omega-Aminoalkyl)-2,2,5,5-tetramethyl-3-pyrroline- or -pyrrolidine-3-carboxamides were acylated on the primary amino group of the side chain by means of reactive acid derivatives (acid chlorides, activated esters, phthalic anhydrides, phthalimide, 2-alkyl-4H-3,1-benzoxazin-4-ones) or they were alkylated by forming the Schiff bases and subsequent sodium borohydride reduction. Other tetramethyl-3-pyrrolinecarboxamide compounds were synthesized by acylating the aminoalkyl compounds with 2,2,6,6-tetramethyl-3,5-dibromo-4-piperidinone in a reaction involving Favorskii rearrangement. Saturation of the double bond of some pyrroline derivatives furnished the pyrrolidinecarboxamides. The new compounds of each type were active against aconitine-induced arrhythmia and several of them had higher activity and better chemotherapeutic index than quinidine. A few selected examples from each type of the active new compounds showed strong activity against ouabain-induced arrhythmia; for comparison known drugs such as lidocaine, mexiletine, and tocainide were selected. The most potent compounds were oxidized to the paramagnetic nitroxides and the latter were reduced to the N-hydroxy derivatives; these products had no or only decreased antiarrhythmic effect.

Animals↗
PubMed1986

Dexamethasone protects against high-dose endotoxin without loss of tolerance to oxygen.

Endotoxin (500 micrograms/kg)-treated rats are very tolerant to hyperoxia (greater than 95% O2, 1 ATA). We have now attempted to determine if dexamethasone given to rats 1 h before a usually lethal dose of endotoxin would diminish endotoxin's lethality without substantially abrogating its capacity to confer tolerance to hyperoxia. Endotoxin (20 mg/kg) given alone killed 70-80% of air- or O2-breathing rats within 24 h; dexamethasone (0.6 mg) given 1 h before endotoxin decreased mortality at 24 h to 10-15%. About 90% of the rats that were alive 24 h after receiving dexamethasone plus endotoxin (20 mg/kg) survived 72 h of hyperoxia. Dexamethasone plus endotoxin (10 mg/kg) provided as much protection against pulmonary edema resulting from 72 h of hyperoxia as did 500 micrograms/kg endotoxin alone. Tolerance to hyperoxia produced by dexamethasone plus high-dose endotoxin was accompanied by a rise in the activity in the lung of antioxidant enzymes. We conclude that dexamethasone protects rats against the lethal effects of high doses of endotoxin without interfering with endotoxin's capacity to engender tolerance to hyperoxia.

Animals↗
PubMed1986

Lung development in the streptozotocin rat fetus: antioxidant enzymes and survival in high oxygen.

Offspring of experimentally induced diabetic animals demonstrate delays in functional, biochemical, and morphological aspects of lung maturation, dealing mainly with the surfactant system. To investigate whether the development of the lung antioxidant enzyme system would be similarly delayed, and thus compromise their tolerance to high O2 exposure, we did the following: 1) produced the diabetic state in rats with streptozotocin injection 24 h after the onset of pregnancy; 2) examined fetal animals from streptozotocin and control rats at gestational days 19, 20, and 21, and newborn animals at day 22 for whole lung disaturated phosphatidylcholine and total phospholipid and for the three antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase; and 3) exposed newborn offspring from streptozotocin-treated and control rats to greater than 95% O2 for several days and their survival, changes in antioxidant enzymes and disaturated phosphatidylcholine and light microscopic findings in response to hyperoxic challenge were compared. Streptozotocin offspring demonstrated essentially no developmental differences in whole lung disaturated phosphatidylcholine, total phospholipid, or antioxidant enzymes activity at the 4 gestational days studied. However, newborns of streptozotocin mothers had consistently superior tolerance to hyperoxic exposure, consisting of increased survival [23/34 (68%) versus 8/26 (31%) in controls, after O2-exposure for 13 days, p less than 0.001], microscopic evidence of reduced inhibition of alveolarization (p less than 0.05), and a trend toward greater antioxidant enzymes response. Thus, in this animal model of experimental diabetes, neither the development of the antioxidant enzymes system nor the development of the surfactant system (as assessed by whole lung disaturated phosphatidylcholine and total phospholipid) appear delayed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Metyrapone delays surfactant and antioxidant enzyme maturation in developing rat lung.

The surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and both can be accelerated by the administration of exogenous glucocorticoids. To test whether the antioxidant enzyme system, like the surfactant system, is regulated, at least in part, by endogenous glucocorticoids, we injected pregnant rats for 3 days prior to delivery with metyrapone, an adrenal 11-beta hydroxylase inhibitor which crosses the placenta and blocks endogenous glucocorticoid synthesis, or saline. Metyrapone offspring had significantly decreased lung tissue disaturated phosphatidylcholine/total phospholipids (p less than 0.05) compared to controls at days 21 and 22 of gestation. Activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were similarly significantly reduced (p less than 0.01) in the lungs of metyrapone offspring at both gestational days studied. One day premature metyrapone pups demonstrated poorer survival than control pups from 25 min after delivery (44% survival versus 83%, p less than 0.05) to 90 min (6% survival versus 78%, p less than 0.01). These findings of delayed maturation of the surfactant and antioxidant enzyme systems following adrenal glucocorticoid blockade suggest that both systems are regulated, at least in part, by an endogenous glucocorticoid mechanism.

Animals↗
PubMed1986

Dexamethasone increases superoxide dismutase activity in serum-free rat fetal lung organ cultures.

Dexamethasone (Dex) injected intraperitoneally to dams on gestational days 19 through 21 significantly enhances the normal late gestational rise of rat pulmonary superoxide dismutase activity. To study if Dex could act directly on lung cells to increase the activity of superoxide dismutase, rat fetal lung organ cultures were established from 21- or 22-day-old pups and maintained in serum free Waymouth 752/1 medium in 95% O2 for 72 h with and without 10 nM Dex in the medium. The cultures increased spontaneously in total superoxide dismutase activity from 17.5 +/- 3.1 to 33.5 +/- 6.2 U/mg DNA during this interval (+90%). The presence of 10 nM Dex caused an increase in enzyme activity to 40.1 +/- 9.3 U/mg DNA (+130%) demonstrating this hormone can act directly on the lung independent of the systemic metabolic consequences of corticosteroid administration. Dex decreased the rate of Cu,Zn superoxide dismutase synthesis (13.5 +/- 3.4 nmol Phe incorporated/mg DNA/h control vs 7.2 +/- 1.6, Dex) and seemed to also decrease the rate of enzyme degradation.

Animals↗
PubMed1985

Endotoxin alters biochemical and morphological responses to pneumonectomy in adult rats.

Adult rats treated with endotoxin, like untreated neonatal rats, are resistant to O2 toxicity and manifest very similar lung biochemical responses. We hypothesized that endotoxin might also alter the adult pneumonectomy response to resemble the accelerated response of younger animals. Adult and 19-day rats underwent pneumonectomy, followed in 24 h by endotoxin or saline injection. Pneumonectomized rats, shams, and controls were killed 72 h after surgery for lung biochemistry and morphometry. Compared with adult saline-pneumonectomized rats, adult endotoxin-pneumonectomized rats, adult endotoxin-pneumonectomized rats demonstrated a significantly greater growth response and a lung biochemical response pattern (increased RNA, markedly increased RNA/DNA) similar to 19-day rats. Morphologically, endotoxin-pneumonectomized rats showed a different pattern of lung regrowth (significantly larger air spaces). Saline pressure-volume curves were not different between the two groups. We conclude that endotoxin administration to pneumonectomized adult rats resulted in accelerated lung regrowth, a lung biochemical response pattern similar to 19-day rats, but a paradoxical morphological pattern resembling more closely that of the adult than the neonatal animal.

Animals↗