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Biomedical subjects

L Frank

Publications and source records attributed to L Frank.

At least 91 records · Page 5Linked to original sources
PubMed1991

Hyperoxic inhibition of newborn rat lung development: protection by deferoxamine.

Prolonged exposure to hyperoxia markedly inhibits normal lung development (alveolarization and respiratory surface area expansion) in immature animals. Since (a) hyperoxia results in excess hydroxyl radical (OH.) formation, (b) (OH.) is implicated in O2-induced lipid peroxidation and DNA alterations, and (c) both OH. formation and its interaction with DNA are Fe++ dependent; chelation of Fe++ should act to protect against pulmonary O2 toxicity and hyperoxic inhibition of lung development. We therefore treated litters of newborn rats with the iron chelator Deferoxamine mesylate (DES) (150 mg/kg/day) during a 10-day exposure to greater than 95% O2. Morphometric analysis demonstrated that compared to the mean airspace size in air control rat pups (Lm = 44.5 microns), hyperoxic exposure resulted in a 34% larger mean air space diameter in O2-saline rat lungs (59.5 microns) versus only an 11% enlargement in O2-DES lungs (51.1 microns*). Lung internal surface area (cm2) per 100-g body weight were air control = 4480, O2-saline = 3570 (decreases 20.3%), and O2-DES = 4125* (decreases 7.9%) (*p less than 0.05 versus O2-saline group). DES-treated animals also had significantly decreased lung conjugated diene levels during hyperoxic exposure and increased lung elastin content (reflective of preserved lung alveolar formation) compared to O2-saline rats. These results indicate that DES treatment substantially ameliorated the inhibitory effects of neonatal hyperoxic exposure on normal lung development.

Aging↗
PubMed1991

Failure of premature rabbits to increase antioxidant enzymes during hyperoxic exposure: increased susceptibility to pulmonary oxygen toxicity compared with term rabbits.

Although the prematurely born are known to have decreased baseline levels of protective antioxidant enzymes (Frank L, Sosenko IRS: J Pediatr 110:9 and 106, 1987), the ability to augment the baseline values during high O2 exposure is the key factor determining O2 tolerance versus O2 susceptibility. We have compared the pulmonary antioxidant enzyme responses of prematurely delivered rabbits (gestational d 29 of 32) and full-term rabbits to 48-72 h of hyperoxic exposure. We found that although full-term newborns exposed to greater than 90% O2 consistently showed elevated superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities, the premature animals repeatedly failed to respond to hyperoxia with increased antioxidant enzyme activity levels. Consistent with the comparative antioxidant enzyme responses were the evidences of O2 toxicity in the two age groups. The prematurely born rabbits had significantly increased lung lavage protein content, lung conjugated diene levels, and more severe light microscopic lung pathology compared with the full-term animals during equal O2 exposure time. This first reported comparison of prematurely born versus full-term animal responses to hyperoxia might help to explain the clinical observation that the very prematurely born infant is excessively prone to the development of O2-induced lung injury and the progressive development of bronchopulmonary dysplasia.

Animals↗
PubMed1991

Premature weaning of rat pups results in prolongation of neonatal tolerance to hyperoxia.

Neonatal rats usually lose their marked tolerance to hyperoxia at about 1 mo of age. We examined the hypothesis that the marked dietary change that occurs at weaning might be important to this loss of O2 tolerance. We, therefore, prematurely weaned rat pups at 15-17 d of age, expecting to find an earlier loss of O2 tolerance. Surprisingly, the prematurely weaned rats showed consistently prolonged relative O2 tolerance compared with normally weaned rats at all ages tested from 35-85 d of life. For example, when challenged with greater than 95% O2 exposure for 7 d, the composite survival rate of the prematurely weaned rats (at 35-85 d of age) was nearly twice that of the normally weaned group (83 of 107 = 78% versus 44 of 107 = 41%, p less than 0.01). In the two experimental groups, nearly all comparative parameters examined were similar, including: 1) growth rate; 2) lung DNA, RNA, and protein; 3) lung antioxidant enzymes and enzyme responses to hyperoxia; 4) lung morphometry; and 5) lung elastin and collagen content. Only serum corticosterone and triiodothyronine levels differed considerably in the two groups. We conclude that premature weaning has a very marked and sustained positive effect on the relative retention of O2 tolerance in the growing rat.

Age Factors↗
PubMed1991

Intralipid increases lung polyunsaturated fatty acids and protects newborn rats from oxygen toxicity.

Intralipid, derived from soybean oil and containing a high percentage of n-6 family polyunsaturated fatty acids (PUFA) and also linolenic acid, an n-3 family PUFA, is commonly the first fat source provided to very low birth weight premature infants. Following up on our previous reports that newborn rats born to dams fed high-PUFA diets demonstrate superior tolerance to hyperoxia, we examined whether the high-PUFA fat source Intralipid might also protect against oxygen toxicity. Adult female rats were fed either regular Rat Chow or fat-free diet containing 20%-Intralipid as the fat source for 3 wk before and then throughout pregnancy and lactation. One- and 5-d-old offspring of Intralipid diet-fed dams demonstrated significant increases in lung lipid n-6 family PUFA plus elevated linolenic acid compared with regular diet-fed offspring. These characteristic fatty acid patterns, apparent in total lung lipids, were even more pronounced in the triglyceride fraction compared with the phospholipid fraction. Associated with these fatty acid changes were significantly improved hyperoxic survival rates (89 out of 95 = 94% survival after 7 d of greater than 95% O2 exposure) in Intralipid offspring (versus 89 out of 106 = 84%, p less than 0.05 in regular diet offspring) and evidence of superior clinical/pathologic status. No differences in pulmonary antioxidant enzyme or surfactant system development, response of antioxidant enzymes to hyperoxic exposure, or lung prostaglandin E2, 6-keto PGF1-alpha or leukotrienes C4-F4 were present. These findings continue to support the hypothesis that increasing lung PUFA content may provide increased O2 free radical scavenging capacity, thus protecting against hyperoxic lung damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Prenatal hormone treatment with thyrotropin releasing hormone and with thyrotropin releasing hormone plus dexamethasone delays antioxidant enzyme maturation but does not inhibit a protective antioxidant enzyme response to hyperoxia in newborn rat lung.

Whereas glucocorticoid administration to pregnant rats produces parallel acceleration of lung surfactant and antioxidant enzyme system maturation in late gestation, prenatal thyroid hormone treatment results in acceleration of surfactant maturation, with a paradoxical decrease in antioxidant enzyme (AOE) development. In these studies, we tested whether prenatal thyroid releasing hormone (TRH) treatment would act like prenatal thyroid hormone on pulmonary surfactant and AOE system maturation and whether combined prenatal treatment with TRH plus dexamethasone (DEX) would alter these effects. Secondly, we tested whether prenatal TRH and prenatal TRH plus DEX would inhibit the ability of newborn rats to respond to hyperoxia with protective increases in AOE activities. Results of the developmental studies revealed significantly increased fetal lung disaturated phosphatidylcholine content with significantly decreased pulmonary AOE activities as a result of prenatal TRH treatment that was not reversed with the addition of DEX. Combined TRH plus DEX treatment resulted in statistically significant decreases in body weight, lung weight, and lung weight to body weight ratios at both 21 and 22 d of gestation; growth effects were not seen with TRH alone. In terms of hyperoxic AOE response, despite being born with lower baseline AOE levels, the newborn animals prenatally treated with TRH or TRH plus DEX were able to induce a normal pulmonary AOE response to high O2 exposure. Although requiring further investigation, this reassuring finding suggests that clinical prenatal therapy with TRH or the combination of TRH plus DEX is not contraindicated for those infants delivered prematurely who go on to require intensive hyperoxic therapy.

Animals↗
PubMed1990

Left ventricular aneurysm with 1- to 2-mm-thick myocardium: a variant of the classic true aneurysm?

From January 1983 to July 1985, 64 patients underwent left ventricular aneurysmectomy in our surgical unit. In 11 (17%) of these cases, the lesion was a variant of the true aneurysm that included an extremely thin (1- to 2-mm), well-defined area of myocardium. In 9 of the cases, the aneurysm was confirmed preoperatively by means of high-quality ventriculography (high resolution and many hues of gray). Surgical and pathologic criteria established the lesion's clinical significance. To the best of our knowledge, these aneurysms constitute a heretofore undescribed variant of the classic true left ventricular aneurysm, exhibiting certain gross characteristics of the false left ventricular aneurysm and sharing with false aneurysms their greater risk of rupture. While it is impossible to tell whether these aneurysms are progressing toward rupture, we believe that all such lesions should undergo urgent repair in the presence of cardiac symptoms. Following aneurysmectomy, ventriculoplasty or septoplasty using an elliptical woven Dacron patch helps to preserve the internal contour and surface anatomy of the ventricle. In our series, this procedure resulted in early and late postoperative mortality figures comparable to those associated with the surgical treatment of classic true left ventricular aneurysms.

Journal Article↗
PubMed1989

Endotoxin increases lung Cu,Zn superoxide dismutase mRNA: O2 raises enzyme synthesis.

Administration of endotoxin to adult rats increases lung Cu,Zn superoxide activity after 72 h of exposure to greater than 95% O2. The increased activity is brought about mainly by a faster rate of Cu,Zn superoxide dismutase synthesis; rats treated with endotoxin but not exposed to hyperoxia do not exhibit these findings (Hass, Frank, and Massaro, J. Biol. Chem. 257: 9379-9383, 1982). We now report that 48 h after treatment of adult rats with endotoxin there was a decreased rate of Cu,Zn superoxide dismutase synthesis by lung slices from air- and O2- exposed rats, although, in both groups, the lung concentration of Cu,Zn superoxide dismutase mRNA was increased approximately 45%. Exposure of endotoxin-treated rats to greater than 95% O2 or air for an additional 24 h (72 h all told) resulted in continued elevation of Cu,Zn superoxide dismutase mRNA only in lungs of O2- exposed rats. In vitro exposure of lung slices from air-breathing saline- or endotoxin-treated rats to 95% O2 for 6 h led to an increased rate of Cu,Zn superoxide dismutase synthesis only in slices from endotoxin-treated rats. We conclude that endotoxin treatment leads to an increased concentration of Cu,Zn superoxide dismutase mRNA in rat lungs, but a sustained elevation of the mRNA, and its translation into an increased rate of Cu,Zn superoxide dismutase synthesis requires exposure of the lung to hyperoxia.

Animals↗
PubMed1989

Thyroid inhibition and developmental increases in fetal rat lung antioxidant enzymes.

After demonstrating that prenatal exogenous thyroid hormone administration to pregnant rats produces decreases in fetal lung antioxidant enzyme (AOE) development despite increases in surfactant development, we examined the role of endogenous thyroid hormones on the development of these two lung systems. We administered the antithyroid drug methimazole (or diluent) to pregnant rats for the final 3 days before premature or term delivery; in a second series of experiments, propylthiouracil was administered for the 10 days before delivery. Both antithyroid drugs, known to cross the placenta, produced significantly decreased thyroid hormone levels in the pregnant dams. Fetal offspring from methimazole-, and propylthiouracil-treated dams demonstrated significant increases in pulmonary superoxide dismutase activity at 20 and 21 days of gestation and in catalase and glutathione peroxidase activities at 21 days compared with control offspring. Surfactant, measured as lung tissue disaturated phosphatidylcholine, was not different between either experimental group and controls. These results suggest that thyroid blockade increases AOE because the influence of thyroid hormone on AOE development may be one of depression. The findings confirm that certain hormonal regulators may influence different developing fetal lung systems in different ways.

Animals↗
PubMed1989

New "rest period" protocol for inducing tolerance to high O2 exposure in adult rats.

We report a new protocol for inducing marked tolerance to prolonged exposure to hyperoxia in adult rats that entails the use of a single "rest period" between exposures to a usually lethal concentration of O2. Exposure of adult rats to greater than 95% O2 for 48 h followed by a rest in air, or a rest even in 50-75% O2, consistently resulted in 100% survival with evidence of only slight pulmonary edema during continuation of exposure to greater than 95% O2 for 3-7 more days (7-day survival for rats rested in room air for 24 h = 23/23; for rats rested in 50-75% O2 for 24 h = 27/27; for continuously O2-exposed control rats = 0/11). Induction of tolerance to hyperoxia was associated with significant increases in the lungs' antioxidant enzyme activities during the reexposure to greater than 95% O2 following the rest period. The molecular means by which the events in this protocol lead to increased lung antioxidant enzyme activity is only partially known, but because of the marked tolerance produced, the elucidation of the mechanisms must be important to our understanding of tolerance to hyperoxia.

Animals↗
PubMed1989

Rat lung Cu,Zn superoxide dismutase. Isolation and sequence of a full-length cDNA and studies of enzyme induction.

The synthesis of Cu,Zn SOD by rat lung increases spontaneously in the fetus in late gestation and during exposure of neonatal and adult rats to greater than 95% O2. To explore the regulation of these increases, we measured rat lung Cu,Zn SOD synthesis and activity. We also cloned and sequenced a rat lung Cu,Zn SOD cDNA that was used to measure Cu,Zn SOD mRNA concentration. We found that (a) under normal gestational and postgestational conditions the synthesis of this enzyme was regulated pretranslationally; (b) the increased synthesis that occurs under hyperoxia (greater than 95% O2), was pretranslationally mediated in otherwise unmanipulated neonatal rats but translationally controlled in hyperoxic adult rats; and (c) in lungs of rats made tolerant to greater than 95% O2 by allowing 24 h rest in air after an initial 48 h in greater than 95% O2, the increased Cu,Zn SOD synthesis that occurred during the second period of hyperoxia was regulated pretranslationally. We conclude Cu,Zn SOD gene expression in the lung is developmentally regulated under normal conditions and in response to an oxidant challenge. Tolerance, whether endogenous or induced, appears to require the accumulation of increased amounts of Cu,Zn SOD mRNA.

Aging↗
PubMed1989

Menhaden fish oil, n-3 polyunsaturated fatty acids, and protection of newborn rats from oxygen toxicity.

We have previously reported that newborn rats born to mothers fed a high n-6 polyunsaturated fatty acid (PUFA) (safflower oil) diet demonstrated increased n-6 PUFA in lung lipids and superior tolerance to high oxygen exposure. In the present study, we explored whether high n-3 PUFA might also protect against hyperoxic damage and by what mechanism. Adult female rats were fed either regular rat chow, a high n-3 (menhaden fish oil-based) diet, or a high n-6 (safflower oil-based) diet for 6 wk before and then throughout pregnancy and lactation. Newborn offspring of the high n-3 (fish oil) dams demonstrated increased n-3 PUFA (i.e. eicosapentaenoic and docosahexaenoic acid) and decreased n-6 PUFA (i.e. linoleic and arachidonic acid) in their lung lipids compared to the other two diet groups. The high n-6 (safflower oil) offspring had the opposite PUFA lung lipid pattern (with increases in total n-6 fatty acids and decreases in total n-3 fatty acids). The high n-3 offspring demonstrated markedly decreased lung levels of prostaglandin E2, F2 alpha and thromboxane B2, whereas the high n-6 offspring had higher eicosanoid levels than the regular diet offspring. Offspring of both high n-6 and high n-3 diet dams demonstrated essentially the same superior hyperoxic tolerance compared to regular diet offspring [7-d (greater than 95% O2) survival rates of 110/115 and 99/109, respectively, versus 70/91, p less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Lack of sex differences in antioxidant enzyme development in the fetal rabbit lung.

A sex difference characterized by a female advantage in the maturation of the fetal pulmonary surfactant system is well documented. Because the surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and share some of the same hormonal regulators, such as glucocorticoids, we questioned whether a sex difference would be present in antioxidant enzyme maturation as it is in surfactant system maturation. We studied fetal rabbits at days 26 and 28 of a 31-day gestational period. Fetal sex was identified histologically. Fetal lung lavage was performed and lavage fluid assayed for phosphatidylcholine, disaturated phosphatidylcholine, and sphingomyelin. Lung tissue from separate fetuses was assayed for disaturated phosphatidylcholine content and total phospholipid content and for the activities of three antioxidant enzymes--superoxide dismutase, catalase, and glutathione peroxidase. No differences were present in antioxidant enzyme maturation between male and female fetal rabbits at the gestational days studied. A female advantage was observed in the lung lavage disaturated phosphatidylcholine/sphingomyelin ratio (at 26 days: female 1.38 +/- 0.42, male 0.99 +/- 0.26; and at 28 days: female 3.29 +/- 0.53; male 2.26 +/- 0.35, p less than 0.05). A female advantage in surfactant development was not reflected in lung tissue disaturated phosphatidylcholine or total phospholipid. We conclude that, unlike the development of the surfactant system, the development of the antioxidant enzyme system in the fetal rabbit lung does not demonstrate a sex difference.

Animals↗
PubMed1988

Polyunsaturated fatty acids and protection of newborn rats from oxygen toxicity.

To test whether polyunsaturated fatty acids (PUFA) might be associated with protection against oxygen toxicity in newborn experimental animals, we performed two series of experiments. In the first series, adult female rats were fed one of three diets--regular Rat Chow, a high-PUFA (safflower oil-based) diet, or a low-PUFA (palm oil-based) diet--for several weeks before and throughout pregnancy and lactation. Newborn offspring of the three diet groups had similar antioxidant enzyme activities and surfactant development. Offspring of dams fed the high-PUFA diet had total lung lipid fatty acids characterized by increased linoleic acid (18:2 omega 6) and arachidonic acid (20:4 omega 6) and a significantly increased PUFA/saturated fatty acid ratio, compared with offspring of dams fed the regular diet or low-PUFA diet; associated with this increased PUFA pattern was markedly superior survival (80 of 84 (95%) vs 56 of 84 (67%) for regular-diet offspring, P less than 0.01) after 7 days in greater than 95% oxygen. Conversely, offspring born to dams fed the low-PUFA diet had decreased lung PUFA content and inferior tolerance to prolonged high O2 exposure (survival 38 of 84 (45%)). In the second experimental series, the postnatal provision of high PUFA rat milk to offspring born to dams fed the low-PUFA diet (via "cross-nurturing" by high-PUFA diet dams) rapidly increased their lung lipid PUFA and improved their hyperoxic survival (44 of 50 vs 25 of 50 for low-PUFA diet newborn animals kept with their low-PUFA mother rats, P less than 0.01). These studies suggest that increasing lung lipid PUFA can confer a protective effect against the toxic effects of hyperoxia on the newborn animal lung.

Animals↗