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Biomedical subjects

D F Tierney

Publications and source records attributed to D F Tierney.

At least 19 recordsLinked to original sources
PubMed1993

Antiproliferative effects on keratinocytes of a range of clinically used drugs with calmodulin antagonist activity.

Thirty-two drugs, including some in use for a variety of clinical disorders, were examined for their ability to inhibit calmodulin activity in vitro. From these, 10 drugs were selected for their inhibition of calmodulin activity and examined for their ability to inhibit proliferation of rapidly dividing human keratinocytes. A significant correlation between antiproliferative activity and calmodulin antagonist potency was found. Of these drugs there were several, including miconazole, dequalinium chloride, bromocriptine and tamoxifen, whose use is well established and well documented. The potential use of these drugs (and others identified in this way) as antipsoriatic agents is discussed.

Calmodulin↗
PubMed1990

Effects of ozone inhalation on polyamine metabolism and tritiated thymidine incorporation into DNA of rat lungs.

We examined the effects of low-level ozone (O3) inhalation on polyamine metabolism and tritiated thymidine (3H-TdR) incorporation into DNA in rat lungs. We have also compared the activities of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, and glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the pentose phosphate cycle and a typical marker of oxidant injury, to assess whether ODC can serve as a sensitive marker of O3 effects on the lung. We exposed 90-day-old male specific-pathogen-free Sprague-Dawley rats to either 0.45 +/- 0.05 ppm (882 +/- 98 micrograms/m3) O3 or filtered room air continuously for 3 days. After exposure, the rats were terminated and the lungs examined for enzyme activities, polyamine contents, DNA content, and 3H-TdR incorporation. We found that in exposed rats, the enzyme activities were significantly increased (p less than 0.05) relative to air controls. G6PD, 25%, ODC, 147%, and S-adenosylmethionine decarboxylase (AdoMet DC), 86%. Polyamine contents were also affected by O3; putrescine increased 80%, p less than 0.05, spermidine did not change, and spermine decreased 23%, p less than 0.05. 3H-TdR incorporation into DNA was significantly elevated, 155%, p less than 0.001, after O3 exposure while total lung DNA content remained unchanged. The concomitant and large increase in ODC activity (reflecting polyamine metabolism) and DNA labeling (reflecting DNA synthesis and/or repair), indicates a strong correlation between the two and suggests that polyamine metabolism may play an important role in the accelerated cell proliferation associated with O3 injury. Moreover, the greater increase in lung ODC activity compared to other enzymes offers a sensitive marker of the lung response to inhaled O3. We conclude that inhalation of O3 at levels similar to what may be encountered during some smog episodes can result in significant pulmonary biochemical alterations with a potential for long-term consequences. The possible association between ODC activity and DNA labeling may offer a new insight into the mechanism of tissue injury and repair. We also speculate that the changes in lung polyamines may reflect antioxidant and anti-inflammatory functions associated with the cellular defense against oxidant injury.

Air↗
PubMed1989

Butyrate increases catalase activity and protects rat pulmonary artery smooth muscle cells against hyperoxia.

A protective effect of butyrate against hyperoxia was found with adult rat pulmonary artery smooth muscle cells. Butyrate (5mM) when added just prior to the hyperoxic exposure (95%) markedly decreased lactate dehydrogenase release from cells during 68 hours of exposure (22% release with butyrate versus 98% without). The uptake and reduction of a tetrazolium compound as another index of cell viability also showed similar improvement with butyrate. Butyrate was associated with a striking increase of catalase to three times the control in the air exposed group while GSH content and the activities of superoxide dismutase and glutathione peroxidase were not significantly changed. In the groups exposed to hyperoxia alone, both enzyme activities were decreased compared to the air exposed controls. When butyrate was present with hyperoxia, the superoxide dismutase was maintained closer to the air exposed control values and the catalase activity remained nearly twice as high as the air exposed control cells. These results suggest that butyrate protects rat pulmonary artery smooth muscle cells from hyperoxia by increasing catalase activity which may help to preserve superoxide dismutase activity. This may be a good model to determine the biological significance of catalase and its interrelationships with other antioxidant systems within the cell.

Animals↗
PubMed1989

Hyperoxia and xanthine dehydrogenase/oxidase activities in rat lung and heart.

Cell injury from hyperoxia is associated with increased formation of superoxide radicals (O2-). One potential source for O2- radicals is the reduction of molecular O2 catalyzed by xanthine oxidase (XO). Physiologically, this reaction occurs at a relatively low rate, because the native form of the enzyme is xanthine dehydrogenase (XD) which produces NADH instead of O2-. Reports of accelerated conversion of XD to XO, and increased formation of O2- formation in ischemia-reperfusion injury, led us to examine whether hyperoxia, which is known to increase O2- radical formation, is associated with increased lung XO activity, and accelerated conversion of XD to XO. We exposed 3-month-old rats either to greater than 98% O2 or room air. After 48 h, we sacrificed the rats and measured XD and XO activities and uric acid contents of the lungs. We also measured the activities of the two enzymes in the heart as a control organ. We found that the activity of XD was not altered significantly by hyperoxia in rat lungs or hearts, but XO activity was markedly lower in the lung, whether expressed per whole organ or per milligram protein, and remained unchanged in the heart. Lung uric acid content was also significantly lower with hyperoxia. The decrease in lung XO activity may reflect inactivation of the enzyme by reactive O2 metabolites, possibly as a negative feedback mechanism. The concomitant decrease in uric acid content suggests either decreased production mediated by XO due to its inactivation or greater utilization of uric acid as an antioxidant. We examined these postulates in vitro using a xanthine/xanthine oxidase system and found that H2O2, but not uric acid, has an inhibitory effect on O2- formation in the system. We therefore conclude that hyperoxia is not associated with increased conversion of XD to XO, and that the exact contribution of XO to hyperoxic lung injury in vivo remains unclear.

Animals↗
PubMed1989

Lung surfactant: some historical perspectives leading to its cellular and molecular biology.

By appreciating the influence of surface forces on lung mechanics, discovering pulmonary surfactant, and then recognizing its deficiency states a small number of investigators began the first 30 years of pulmonary surfactant research. These investigators had different backgrounds and took diverse approaches to understand surface forces in the lung. Their careers provide a fascinating study of the means by which new discoveries are made. After recognizing the critical importance of surfactant, investigators turned to a series of questions that obviously needed to be answered and they attempted to learn the following: 1) how to quantitate surfactant; 2) its biochemical and structural composition; 3) how it leaves the alveolar surface after secretion; and 4) its role in lung diseases. This research established the basis for pursuing the cellular and molecular biology of surfactant.

Animals↗
PubMed1989

Polyamines, DNA synthesis, and tolerance to hyperoxia of mice and rats.

Adaptation to hyperoxia has been attributed to increased activities of protective enzymes, but we suggest that an additional factor may be the lung's capacity to repair itself in hyperoxia. Such repair would require increased polyamines, but there are reports that two key enzymes of polyamine metabolism are suppressed by hyperoxia or oxidants. Because rats can adapt to hyperoxia but mice cannot, we compared their changes of polyamine metabolism and judged cell repair by using [3H]thymidine to estimate DNA synthesis. Both species developed increased ornithine decarboxylase activity and putrescine content, but the mouse did not develop increased S-adenosylmethionine decarboxylase activities or increases of spermidine and spermine as did the rat when exposed to 85% O2. Furthermore, we confirmed that the rat lung does respond to hyperoxia with increased DNA synthesis, but the mouse lung does not. The results suggest that in addition to increased activities of protective enzymes, increased repair processes in the rat lung may play a role in its capacity to adapt to hyperoxia. The incomplete response of polyamine metabolism in mice may contribute to their inability to adapt in hyperoxia.

Adaptation, Physiological↗
PubMed1988

Effects of food restriction and hyperoxia on rat survival and lung polyamine metabolism.

We fed Sprague-Dawley rats either freely or by restricting them to 20% of their usual diet for 21 days. In one experiment, we refed half of the food-restricted rats for 12 h, then exposed the three groups to air or 85% O2 for 5 days. The mortalities in 85% O2 were 100, 33, and 0% for the food-restricted, restricted-refed, and freely fed groups, respectively. In air lung polyamine contents and glucose 6-phosphate dehydrogenase and NADP-dependent isocitrate dehydrogenase activities were significantly lower with food restriction. After hyperoxia, lung polyamine and protein contents and enzyme activities were increased in the two surviving groups, but spermine and DNA contents of refed rats did not increase. In a second experiment, we exposed rats to 60% O2 and found that DNA synthesis of food-restricted rats was lower than the freely fed rats in air and remained low after hyperoxia. We conclude that food restriction increases the mortality from 85% O2 and is associated with lower DNA synthesis and polyamine content. We speculate that food-restricted animals may accumulate greater lung injury partly because of a compromised repair process.

Animals↗
PubMed1987

Lung phospholipids during recovery from oxygen toxicity are altered by hydrocortisone.

Corticosteroids affect type II alveolar epithelial cells, increase the lung's content of lipids associated with pulmonary surfactant, and have been used to treat the adult respiratory distress syndrome. We used hyperoxia to produce diffuse alveolar damage in rats and then determined the contents of lung lipids and the incorporation of precursors into these lipids while the rats recovered in air and received either hydrocortisone or saline injections. With saline injections (control) the total lipid content after hyperoxia and 48 hours recovery in air was nearly twice the lipid content of lungs never exposed to hyperoxia; many lipids, including phosphatidylcholine (PC), shared in this increase. With hydrocortisone injections the total lipid content, when expressed per lung, was not significantly greater than with saline injections but when expressed per mg DNA several lipid subgroups, including phosphatidylcholine, were significantly greater. Palmitate incorporation into most lipids of lung slices was not significantly different by 48 hours of recovery, and hydrocortisone had a modest effect after 96 hours. In contrast to the incorporation of palmitate, the incorporation of glycerol and of lysophosphatidylcholine (LPC) nearly doubled in most lipids during the recovery phase. Hydrocortisone injections were associated with greater glycerol incorporation after 96 hours of recovery in nearly all lipids and LPC incorporation was increased primarily into PC. We conclude that lung lipids increase markedly during recovery from severe oxygen toxicity and that hydrocortisone leads to additional increases of saturated and unsaturated PC.

Animals↗
PubMed1985

Hyperoxic lung injury and polyamine biosynthesis. Age-related differences.

To determine if lung cell replication and repair might be different between younger (30-day-old) and older (60-day-old) rats, we studied polyamine and DNA biosynthesis in rats exposed to 1.0 atm oxygen for 24, 48, 56, or 72 h. By 24 h, no statistically significant changes were observed, but by 48 h, ornithine decarboxylase and putrescine increased; S-adenosylmethionine decarboxylase activity increased by 56 h in the younger rats but not in the older rats. By 72 h, spermidine, [3H]thymidine incorporation, and the labeling index of cells in the alveolar zone had increased only in the younger rats. During the first 56 h, hyperoxia inhibited DNA synthesis. We conclude that hyperoxia initially suppresses lung cell replication but subsequently, if the rat survives, there are increases in polyamine biosynthesis and cell replication that may be important for the development of oxygen tolerance.

Adenosylmethionine Decarboxylase↗
PubMed1985

Polyamines in clinical disorders.

An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles. The Director of Conferences is William M. Pardridge, MD, Associate Professor of Medicine.Polyamines, necessary for cell growth, influence many cell functions. As small polyvalent cations they can change the configuration of large polyvalent anions, such as DNA, and alter their sensitivity to other molecules including chemotherapeutic agents. By altering polyamine content in a cell, we can change its growth, its susceptibility to drugs and change other cellular functions. Malignant conditions, other proliferative diseases and infections are the most apparent clinical conditions likely to improve by depleting polyamines and suppressing cell growth. Proliferative disorders of the skin respond to many agents that suppress polyamine metabolism. Hyperoxia may suppress cell growth in the lung by suppressing polyamine metabolism.

Animals↗
PubMed1984

Cyclic nucleotide concentrations in tissue and perfusate of isolated rat lung.

Cyclic nucleotide content of lung tissue is altered by anesthesia, ventilatory pattern, and pharmacologic manipulation (e.g., isoproterenol). In addition the lung releases cyclic nucleotides into its circulation, but little is known about factors that might alter this release. We isolated and perfused rat lungs (IPL) to determine: 1) if cyclic nucleotides are released into the perfusate in the control state; and 2) if their release changes after alteration of the ventilatory pattern or the addition of isoproterenol. We demonstrated that the rat IPL releases both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into the perfusate. Isoproterenol has no effect on cGMP release but increases cAMP release dramatically. Perfusate cAMP is not affected by ventilatory pattern, but perfusate cGMP is higher during high-pressure ventilation than it is in nonventilated or normally ventilated lungs.

Animals↗
PubMed1983

Polyamine metabolism in rat lungs with oxygen toxicity.

Ornithine decarboxylase activity increases 2-fold above control after 1 day and 25-fold after 3 days of exposure to 0.85 atm oxygen. Putrescine content nearly doubled by 72 hours which may reflect increased activity or ornithine decarboxylase. Spermidine and spermine content did not increase until after 3 days of exposure which was consistent with the delayed increase of S-adenosylmethionine decarboxylase activity. The results suggest that antimetabolites of polyamine metabolism may be useful to suppress excessive cellular proliferation in the lung after acute lung injury.

Animals↗
PubMed1983

Poor correlation between oxygen toxicity and activity of glutathione peroxidase.

To test the postulate that increased activity of the glutathione peroxidase system is required for the increased tolerance to oxygen toxicity that develops after several days of prior exposure to 85% oxygen we searched for a combination of increased tolerance but normal activity of the glutathione system. We exposed rats to 85% oxygen for 7 days and then placed them in air. After 0, 10, 20, and 30 days we estimated the potential role of an antioxidant system by measuring activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GP), and the nonprotein sulfhydryl content (NPSH) of lung tissue. After 7 days in 85% oxygen (0 days in air) activities of G6PD, GR, and GP, were elevated above control values by 189%, 32%, and 126%, respectively, and NPSH was 146% higher. Twenty days later these activities and NPSH were not significantly different from those of control animals never exposed to 85% oxygen. We also tested these rats without increased enzyme activities for oxygen "tolerance" by exposing them, after 20 days of recovery in air, to 100% oxygen for 3 days and found that some were "tolerant" as judged by a mortality rate of only 42% compared with 100% in a group not previously exposed to oxygen. To determine if this degree of tolerance could be related to accelerated increases of enzyme activities during the exposures we measured the enzyme activities and NPSH of lungs at 12, 24, 36, 48 and 60 hr after the start of exposure to 100% oxygen in two groups: one preexposed to 85% oxygen 20 days earlier and the other not previously exposed to oxygen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Adult respiratory distress syndrome.

Many causes for the adult respiratory distress syndrome (ARDS) have been reported, all with common pathologic, pathophysiologic and biochemical end results. The final common pathway may involve changes in lung content of a critical enzyme, superoxide dismutase, or alterations in surfactant metabolism, or both. The early assumption that the disorder is partially due to oxygen toxicity from inspired oxygen concentrations greater than 60 percent is consistent with findings of recent biochemical studies. Although the lung normally maintains its alveoli dry, during ARDS increased permeability of small pulmonary vessels results in primary pulmonary edema, in contrast to edema from increased vascular pressure. These data have been obtained mainly in animals; whether they apply to humans with ARDS is not certain. Tissue oxygenation is improved by increasing end-expiratory pressure in an animal model of ARDS, more effectively during spontaneous breathing than during mechanical ventilation. During spontaneous breathing, adverse ventilatory effects were caused by stimulation of pulmonary reflexes.

Humans↗
PubMed1979

Oxygen toxicity.

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Animals↗