Biomedical subjects

S L Young

Publications and source records attributed to S L Young.

At least 37 records · Page 2Linked to original sources

PubMed1997

Expression of transforming growth factor-beta receptors during hyperoxia-induced lung injury and repair.

Lung injury and repair processes involve many cellular activities, including cell growth, differentiation, and remodeling of extracellular matrix components. Transforming growth factor-beta (TGF-beta) is a major class of signaling peptide growth factors regulating these cellular activities. Type I (T beta RI) and type II (T beta RII) receptors for TGF-beta are transmembrane serine/threonine kinases that are essential for TGF-beta signaling. To gain insight into the possible molecular mechanisms of lung injury and repair, we investigated the expression of T beta RI and T beta RII in an acute hyperoxia-induced model of lung injury and repair. Localization of message expression of T beta RI and T beta RII in oxygen-exposed rat lung tissue was analyzed by using in situ hybridization. T beta RI mRNA expression was found in the interstitium, capillaries, and the alveolar septa of rat lungs exposed for 60 h to 100% oxygen. The distribution of T beta RII mRNA in oxygen-exposed rat lung tissue overlapped the localization of T beta RI mRNA. Temporal changes of T beta RI and T beta RII mRNA expressions in rat lung during hyperoxic exposure and repair were examined by Northern analysis. We found that expression of T beta RI was upregulated in adult rats undergoing prolonged exposure to 100% oxygen, and the increase of T beta RI expression persisted during 2 wk of repair of lung injury. The pattern of T beta RII expression during hyperoxic exposure and repair was distinct from that of T beta RI. The expression of T beta RII increased with a peak at 3 days postexposure and then declined after 7 days of repair. Changes of T beta RI and T beta RII protein expressions in rat lung during hyperoxic exposure and repair were examined further by Western blot analysis, which correlated with the mRNA expression. The results suggest that T beta RI and T beta RII may play important roles during the lung injury and repair by mediating signaling activity of TGF-beta and may regulate interactions between the mesenchyme and the epithelium.

Animals↗

PubMed1996

Identification and developmental expression of two activin receptors in baboon lung.

Activins are members of the transforming growth factor-beta (TGF-beta) superfamily that exert their effects through interacting with specific cell surface TGF-beta superfamily receptors (TSRs). To determine whether activins are involved in lung development, we used a reverse transcription polymerase chain reaction (RT-PCR)-based approach to identify members of the activin receptors from baboon fetal lung mRNAs. Two partial cDNA sequences encoding serine/threonine kinase domains of baboon TSR type I (bTSR1) and type II (bTSR2) were identified by sequencing analysis. bTSR1 displays 96% identity to human activin type I receptor TSR1, whereas bTSR2 shows 80% identity to human activin type II receptor ActRIIB over the kinase domain region. Northern analysis revealed the expression of a 2.1 kb bTSR1 transcript and a 5.0 kb bTSR2 transcript in baboon lung tissues. Both bTSR1 and bTSR2 were expressed throughout embryonic lung development and in adult lung. The expressions of bTSR1 and bTSR2 were developmentally regulated and each had a distinct expression pattern. Furthermore, the expressions of bTSR1 and bTSR2 in fetal baboon lung were altered by oxygen exposure. This study for the first time identifies the presence of the activin receptors in the baboon lung and provides evidence that both bTSR1 and bTSR2 are regulated during lung development, suggesting that activins might play an important role during lung development.

Activin Receptors↗

PubMed1996

Requirement of transforming growth factor-beta (TGF-beta) type II receptor for TGF-beta-induced proliferation and growth inhibition.

Growth regulation of fibroblasts is important for lung development and repair of lung injury. In this study, we investigated the role of transforming growth factor-beta (TGF-beta) type II receptor in the TGF-beta-dependent proliferative response of lung fibroblasts. TGF-beta stimulated the proliferation of adult lung fibroblasts at a low concentration (1 ng/ml), but inhibited the growth of fetal lung fibroblasts in a dose-dependent fashion (0.1-10 ng/ml). Cross-linking and Northern analysis demonstrated that the two lung fibroblast cell lines expressed the TGF-beta type I receptor (T beta RI) and type II receptor (T beta RII). We overexpressed in lung fibroblasts a truncated derivative of T beta RII that lacked the cytoplasmic serine/threonine kinase domain (T beta RII delta K). T beta RII delta K was a dominant-negative inhibitor of TGF-beta signal transduction blocking not only TGF-beta-induced mitogenic action upon adult lung fibroblasts but also TGF-beta-induced growth inhibition of fetal lung fibroblasts. The results indicate that the type II receptor is indispensable for mediating both the mitogenic and antiproliferative effects of TGF-beta upon lung fibroblasts.

Animals↗

PubMed1996

VA/Q abnormalities during gram negative sepsis.

Hypoxemia in bacterial sepsis develops by mechanisms which are incompletely understood. In this study, we measured pulmonary gas exchange in eight baboons to determine the causes of hypoxemia after infusion of live Escherichia coli (1 x 10(10) CFU/kg) followed by resuscitation with intravenous fluid. VA/Q distributions were measured periodically using the multiple inert gas elimination technique until death or for a maximum of 42 h. After E. coli infusion, dispersion of perfusion (logSDq) increased rapidly and a transient rise in dead space was observed at 6 h coinciding with systemic hypotension and acidosis. The intrapulmonary shunt developed later and reached 27 +/- 6% at 24 h. PaO2 began to decrease at 12 h and correlated with increases in intrapulmonary shunt and logSDq. There was no evidence of diffusion limitation. Lung edema was mild despite aggressive fluid resuscitation. Morphometric analysis of postmortem lungs revealed dramatic intravascular accumulation of granulocytes. There were increases in arithmetic mean thicknesses of epithelium and interstitium. These data indicate that gram negative sepsis with fluid resuscitation causes progressive hypoxemia, primarily due to the development of intrapulmonary shunt and very low VA/Q regions in the lung. The VA/Q abnormalities occur early and likely reflect ongoing cellular responses in pulmonary vasculature and smaller airways in sepsis.

Animals↗

PubMed1996

Composition of lung lavage in pulmonary alveolar microlithiasis.

A case of pulmonary alveolar microlithiasis (PAM) is reported wherein total lung lavage was performed for relief of dyspnea. Characterization of the lavage material and examination of the microliths isolated from the lavage fluid confirmed previous reports of their spherical-ovoid shape and a 2:1 calcium to phosphate composition. The microliths contained considerable amounts of ionizable iron and generated oxidants in an in vitro system. A detailed biochemical analysis of the lavage fluid reflected elevations in total protein, phosphatidylserine, phosphatidylglycerol and the ratio of phosphatidylglycerol to phosphatidylinositol. Surfactant apoprotein-A levels approximated that of normal patients. The potential roles of oxidant generation and alterations in surfactant metabolism are discussed in the context of the pathogenesis of PAM.

Adult↗

PubMed1995

Scopolamine impairs acquisition and facilitates consolidation of fear conditioning: differential effects for tone vs context conditioning.

Cholinergic antagonism impacts selected learning tasks. To understand where scopolamine exerts its action, learning tasks differentially sensitive to hippocampus and amygdala lesions were used. Hippocampal lesions prevent context fear conditioning without effect on tone conditioning. These lesions also produce a time-dependent retrograde deficit in context conditioning. The amygdala is necessary for both tone and context conditioning. To examine the possibility that cholinergic antagonism mimics hippocampal damage or amygdala damage, rats were given scopolamine (1 mg/kg) either before or after fear conditioning. In the fear conditioning procedure, rats received tone-footshock or context-footshock pairings. Evidence of conditioning to the tone and the context was provided by observation of freezing. When given prior to training, scopolamine blocked fear conditioning to the tone in a dose-dependent fashion but had no effect on context conditioning. The impairment of tone conditioning did not occur with methylscopolamine, indicating the central action of the drug. Rats given scopolamine immediately following fear conditioning, tested later in a drug-free state, froze more to the tone than rats given a control injection. The effect of scopolamine on freezing to the context was not reliable. The present results suggest that scopolamine's impact on fear conditioning is mediated by some mechanism other than impaired hippocampal or amygdala functioning.

Acoustic Stimulation↗

PubMed1995

TGF-beta regulates expression of tenascin alternative-splicing isoforms in fetal rat lung.

Two distinct mRNA-splice isoforms of tenascin (TN) are expressed differentially during rat lung development. The unique temporal expression pattern of two TN isoforms suggests the expression of tenascin is strictly developmentally regulated in rat lung tissue. We investigated molecular mechanisms which modulate alternative-splicing expression of TN in lung development. The effect of transforming growth factor-beta 1 (TGF-beta 1) on regulation of expression of TN isoforms was examined by in vitro lung explant culture. Immunoblotting with anti-TN antibody detected two TN polypeptides in rat lung explant culture, the larger [relative molecular weight (M(r)) 230, TN230] polypeptide and the smaller (M(r) 180, TN180). TGF-beta 1 markedly induced the TN180 isoform and caused only a moderate increase of the TN230 isoform. The effects of TGF-beta 1 were shown to be dose dependent over a physiological range of TGF-beta 1 protein concentration. The induction of TN isoform biosynthesis by TGF-beta 1 was detected 12 h after addition of the growth factor, and the effects endured for up to 48 h at a dose of 5 ng/ml. By reverse transcriptase-polymerase chain reaction through amplification of the entire fibronectin type III (FN-III) splicing domain, two distinct TN isoforms were detected in total RNA isolated from gestational day 21 rat lung explant culture treated with TGF-beta 1 and from postnatal day 8 rat lung. The larger isoform contained five FN-III alternative splicing repeats [1,420 base pairs (bp)], but the shorter splicing isoform lacked four FN-III alternative splicing repeats (340 bp).(ABSTRACT TRUNCATED AT 250 WORDS)

Alternative Splicing↗

PubMed1995

An age-related difference in hyperoxia lethality: role of lung antioxidant defense mechanisms.

The role of animal age in the lethal response to > 98% oxygen has been extensively studied, with the observation that neonatal rats were resistant while mature animals were sensitive. Antioxidant enzymes increased during the oxygen exposure in neonatal but not in mature rats, suggesting they were important in the age-related toxicity difference. Because no studies had compared the response of mature and old rats to hyperoxia, we exposed Fischer 344 rats, aged 2 and 27 mo, to > 98% oxygen. Unexpectedly, the old rats lived significantly longer than young, 114 and 65 h, respectively. No histopathological differences were found to explain the results. Of the antioxidants, only glutathione peroxidase (GPx) activity was higher in the lungs of nonexposed old rats. Superoxide dismutase (SOD) was higher in the young, results opposite those expected if SOD was important in the lethality difference. No antioxidant induction occurred in the old oxygen-exposed rats. These results suggest that although there may be a role for GPx, mechanisms in addition to antioxidant protection and inflammation are likely responsible for the age-related difference in hyperoxia lethality.

Aging↗

PubMed1995

Expression of transforming growth factor-beta type II receptor in rat lung is regulated during development.

Transforming growth factor-beta (TGF-beta) is an autocrine/paracrine growth factor that regulates cell proliferation, differentiation, extracellular matrix production and various other cell functions in the lung. TGF-beta exerts its effects on cells by binding to transmembrane heteromeric serine-threonine kinase receptors. The expression and localization of specific TGF-beta receptors in the lung, however, have not yet been investigated. In the present studies, we isolated a 1,762-base pair cDNA containing the full-length coding sequence for TGF-beta type II receptor (T beta RII) from rat fetal lung with the use of polymerase chain reaction methods. The expression of T beta RII during lung development was examined by Northern analysis. A 5.1-kilobase T beta RII mRNA was detected in rat lung tissue. T beta RII mRNA was expressed in rat fetal lung tissue early in development, increased as development proceeded, reached maximal concentration postnatally, and then decreased to the adult level. The localization of T beta RII in fetal and postnatal rat lung tissue was investigated with the use of in situ hybridization performed with an antisense RNA probe. T beta RII gene was expressed in the mesenchymal tissue and in the epithelial lining of the developing airway at day 16 of gestation. The hybridization signal of T beta RII mRNA was also observed in the adventitial layer of small blood vessels. Expression of T beta RII gene in the developing airway epithelium occurred along a proximal-distal gradient. In postnatal lung, T beta RII mRNA was detected mainly in parenchymal tissues and blood vessels. Expression of T beta RII remained high in the interstitium of interalveolar septa.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1995

Tenascin in rat lung development: in situ localization and cellular sources.

Tenascin (TN) is a hexameric extracellular matrix glycoprotein that may play an important role during lung development. TN protein is temporally and spatially restricted during lung organogenesis. The temporo-spatial and cellular expression of TN mRNA in lung remains unclear. Localization of message expression of TN in rat lung tissue was first investigated by using in situ hybridization performed with an antisense RNA probe. TN mRNA was present primarily within the mesenchyme of day 16 gestational age fetal rat lung tissue, whereas immunoreactive TN protein was found along the basement membrane. In postnatal day 3 rat lung tissue, TN mRNA was detected along alveolar septal walls and was concentrated at secondary septal tips. Expression of TN message was consistent with localization of immunoreactive TN protein. Accumulation of TN mRNA in alveolar septal tips suggests that mesenchyme may be the major source of TN mRNA. To investigate the cellular source of TN in rat lung, we studied the expression of TN in cultured rat lung fibroblasts, endothelial cells, and alveolar epithelial cells. Two TN isoforms having molecular mass of 230 and 180 kDa were in conditioned medium and in cellular extracts of lung fibroblasts and endothelial cells. TN was secreted and deposited in the extracellular matrix closely associated with the surface of lung fibroblasts and endothelial cells. Lung alveolar epithelial cells showed undetectable or barely detectable amounts of TN. These studies demonstrated that TN isoforms are expressed not only by lung fibroblasts but also by lung endothelial cells. The unique spatial localization of TN mRNA during lung development and expression of TN by different lung cell types suggested TN may be involved in matrix organization and cell-cell interactions during lung development.

Aging↗

PubMed1995

Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry.

Prolonged exposure to O2 causes diffuse alveolar damage and surfactant dysfunction that contribute to the pathophysiology of hyperoxic lung injury. We hypothesized that exogenous surfactant would improve lung function during O2 exposure in primates. Sixteen healthy male baboons (10-15 kg) were anesthetized and mechanically ventilated for 96 h. The animals received either 100% O2 (n = 6) or 100% O2 plus aerosolized artificial surfactant (Exosurf; n = 5). A third group of animals (n = 5) was ventilated with an inspired fraction of O2 of 0.21 to control for the effects of sedation and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion distribution (VA/Q) was measured daily using a multiple inert-gas elimination technique. Positive end-expiratory pressure was kept at 2.5 cmH2O and was intermittently raised to 10 cmH2O for 30 min to obtain additional measurements of VA/Q. After the experiments, lungs were obtained for biochemical and histological assessment of injury. O2 exposures altered hemodynamics, progressively worsened VA/Q, altered lung phospholipid composition, and produced severe lung edema. Artificial surfactant therapy significantly increased disaturated phosphatidylcholine in lavage fluid and improved intrapulmonary shunt, arterial PO2, and lung edema. Surfactant also enhanced the shunt-reducing effect of positive end-expiratory pressure. We conclude that an aerosolized protein-free surfactant decreased the progression of pulmonary O2 toxicity in baboons.

Animals↗

PubMed1995

Artificial surfactant attenuates hyperoxic lung injury in primates. II. Morphometric analysis.

Diffuse lung injury from hyperoxia is accompanied by low compliance and hypoxemia with disruption of endothelial and alveolar epithelial cell layers. Because both function and content of surfactant in diffuse lung injury decrease in animals and in humans, changes in the extent of injury during continuous hyperoxia were evaluated after treatments with a protein-free surfactant in primates. Ten baboons were ventilated with 100% O2 for 96 h and five were intermittently given an aerosol of an artificial surfactant (Exosurf). Physiological and biochemical measurements of the effects of the surfactant treatment are presented in a companion paper (Y.-C. T. Huang, A. C. Sane, S. G. Simonson, T. A. Fawcett, R. E. Moon, P. J. Fracica, M. G. Menache, C. A. Piantadosi, and S. L. Young. J. Appl. Physiol. 78: 1823-1829, 1995.) After O2 exposures, lungs were fixed and processed for electron microscopy. The cellular responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. Morphometry was used to quantitate changes in lungs of animals treated with the artificial surfactant during O2 exposure and to compare them with the untreated animals. The surfactant decreased neutrophil accumulation, increased fibroblast proliferation, and decreased changes in the volume of type I epithelial cells. Surfactant-treated animals also demonstrated better preservation of endothelial cell integrity. These responses indicate ameliorating effects of the surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction. Significant interstitial inflammation and fibroblast proliferation remained, however, in surfactant-treated lungs exposed to continuous hyperoxia.

Aerosols↗

PubMed1995

Development of pediatric and neonatal parenteral nutrition order forms.

The diversity of nutritional needs within the pediatric population makes ordering parenteral nutrition (PN) for infants and children a difficult task for inexperienced clinicians. A well designed PN order form can simplify this task. Standard PN solutions, tables with age-specific nutrient requirements, and guidelines for advancing substrate may improve PN prescriptions and serve as an educational tool. The development of an optimal PN order form for an institution requires consideration of many factors, including the patient population, requirements of the institution, and the needs of the staff and students. One nutrition support team's experience in developing pediatric PN order forms is described.

Age Factors↗

PubMed1994

The stimulation of cellular phospholipid uptake by surfactant apoproteins.

Surfactant recycling by alveolar cells is influenced by the surfactant apoproteins SP-A, -B and -C (Wright, J.R. and Dobbs, L.G. (1991) Annu. Rev. Physiol. 53, 395-414). Alveolar macrophages and type II cells, but not lung fibroblasts, were reported to accumulate surfactant phospholipid in the presence of SP-A in low calcium medium, although high affinity binding of SP-A to alveolar macrophages and type II cells showed an absolute requirement for mM calcium. SP-B, one of two very hydrophobic surfactant proteins, stimulated phospholipid uptake by type II cells and Chinese hamster lung fibroblasts suspended in Dulbecco's minimum essential medium containing mM Ca2+. We postulated that calcium influences cellular phospholipid uptake stimulated by SP-A or SP-B. We used isolated rat alveolar and peritoneal macrophages and Vero cells, an African Green Monkey kidney fibroblast cell line, and studied the effect of calcium concentrations ranging from 2 microM to 2 mM on cellular uptake of liposomes containing 3H-labeled phosphatidylcholine. For alveolar and peritoneal macrophages, increasing calcium concentration enhanced SP-A stimulation of phospholipid uptake. SP-A did not stimulate phosphatidylcholine uptake by Vero cells. SP-B stimulated phosphatidylcholine uptake by alveolar and peritoneal macrophages and Vero cells independent of the calcium concentration. These studies demonstrate that the enhancement of phospholipid uptake in alveolar and peritoneal macrophages by SP-A, but not SP-B is augmented by calcium.

Animals↗

PubMed1994

Pavlovian conditioning alters cortical microtubule-associated protein-2.

Three experiments indicate that Pavlovian conditioning to tone alters microtubule-associated protein-2 (MAP-2) in the temporal cortex. First, increased MAP-2 immunohistochemistry was evident in temporal cortex following tone-shock pairings but not light-shock pairings. In the second experiment, animals given tone paired with shock (compared with animals trained with tone unpaired with shock or given tone only) showed MAP-2 immunohistochemical changes in the temporal cortex, as well as in the frontal and cingulate cortex, the hippocampus and amygdala. In experiment 3, quantitative immunoblots showed decreased intact MAP-2 and increased breakdown products selectively in temporal cortex following fear conditioning to tone. Conditioning to tone also increased sizes of MAP-2 rich pyramidal somata and apical dendrites in temporal and frontal cortex.

Acoustic Stimulation↗

PubMed1994

Tenascin-C in rat lung: distribution, ontogeny and role in branching morphogenesis.

Extracellular matrix is important to organogenesis and may function by modifying cellular adhesion, motility, proliferation, and differentiation. Tenascin-C (TN-C) is a matrix molecule reported to bind some cell lines and to inhibit adhesion of some cell types to fibronectin. This report describes the ontogeny and possible functions of TN-C expression in fetal and newborn rat lung. There was a moderate concentration of TN-C protein at the epithelial-mesenchymal interface during fetal lung development in the period of branching morphogenesis. There was a remarkable accumulation of TN-C during the first postnatal week when alveolarization peaked, followed by a decline to barely detectable levels after the third postnatal week when alveolarization was essentially completed. Loss of TN-C protein followed quickly the loss of TN-C mRNA, suggesting a rapid turnover of TN-C in the extracellular matrix. By light microscopy, immunoreactive TN-C was present in early postnatal lung at the epithelial-mesenchymal interface and was distributed throughout lung mesenchyme. Electron microscopic immunocytochemistry showed TN-C was not a part of the basal lamina and that its lung localization was punctate and different from the uniform distribution of laminin. Antiserum to TN-C significantly inhibited branching morphogenesis of fetal lung explants but did not block their growth. Three bacterially expressed segments of TN-C comprising different fibronectin type III domains inhibited branching morphogenesis as effectively as did antiserum, but an expression protein of the carboxyterminal fibrinogen-like segment had no effect. We conclude that TN-C is expressed in a spatio-temporal pattern consistent with a role in lung development and our in vitro studies indicated a functional role for TN-C during lung branching morphogenesis.

Age Factors↗

PubMed1994

The effect of alternative product-label design on warning compliance.

Many potentially hazardous products are packaged in small containers. Because of the limited amount of space available on these containers for warnings and other information, manufacturers often reduce the size and amount of printed material on the labels. This frequently impairs the message's legibility, noticeability and comprehensibility. Recently, several alternative label designs have been investigated using preference ratings, but whether the designs facilitate safer behaviour has not been determined. In the present experiment, two alternative designs (tag and wings) were compared with a conventional (control) design for their effect on behavioural compliance with a warning on a very small container of glue. Participants performed a parts-assembly task using the glue without being informed of the study's real purpose. Whether participants wore protective gloves as directed by the warning was measured. Results showed that the tag design produced significantly greater compliance than the other two designs. Measures of noticing, reading and recall of the warning mirrored the compliance results. While participants generally preferred the control label, they most preferred the tag warning. Overall, the results suggest that alternative designs like the tag can enhance warning communication and compliance in cases where surface area is limited.

Journal Article↗

PubMed1994

NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: immunization against amnesia by context preexposure.

Hippocampal lesions in rats produce both a retrograde and an anterograde amnesia of contextual fear conditioning. The present experiments examined the anterograde deficit in context conditioning. The deficit produced by electrolytic hippocampal lesions was apparent when training occurred on 7, 14, or 28 days following surgery, confirming the durability of the amnesia. The role of the hippocampus in context conditioning may be related to an NMDA (N-methyl-D-aspartate) receptor-mediated process. Both NMDA hippocampal lesions and intrahippocampal administration of an NMDA antagonist produced anterograde amnesia. Animals preexposed to the conditioning context 28 days prior to hippocampal lesioning were protected from the deficit normally produced by the lesions. Thus, the hippocampus must form a contextual representation during preexposure that is subsequently stored elsewhere. Once formed this representation of the context can be associated with an unconditional stimulus.

Animals↗