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1.  Toward Therapeutic Pulmonary Alveolar Regeneration in Humans 
In humans, age results in loss of pulmonary alveoli; menopause accelerates loss of diffusing capacity, an index of alveolar surface area; and disease (e.g., chronic obstructive pulmonary disease) results in loss of alveoli. Thus, an important goal for investigators is to generate knowledge that allows induction of pulmonary alveolar regeneration in humans. Our enthusiasm for this goal and our assessment of its feasibility are based on work in several laboratories over the last decade that has disproved the notion that pulmonary alveoli are incapable of regeneration, and on the growing evidence that signals that regulate programs of alveolar turnover (loss and regeneration) are conserved from rodents to humans. We review animal models of alveolar loss and regeneration and their conservation during evolution, and hence their relevance to humans.
PMCID: PMC2647657  PMID: 17065378
age; chronic obstructive pulmonary disease; menopause
2.  The PEPR GeneChip data warehouse, and implementation of a dynamic time series query tool (SGQT) with graphical interface 
Nucleic Acids Research  2004;32(Database issue):D578-D581.
Publicly accessible DNA databases (genome browsers) are rapidly accelerating post-genomic research (see, with integrated genomic DNA, gene structure, EST/ splicing and cross-species ortholog data. DNA databases have relatively low dimensionality; the genome is a linear code that anchors all associated data. In contrast, RNA expression and protein databases need to be able to handle very high dimensional data, with time, tissue, cell type and genes, as interrelated variables. The high dimensionality of microarray expression profile data, and the lack of a standard experimental platform have complicated the development of web-accessible databases and analytical tools. We have designed and implemented a public resource of expression profile data containing 1024 human, mouse and rat Affymetrix GeneChip expression profiles, generated in the same laboratory, and subject to the same quality and procedural controls (Public Expression Profiling Resource; PEPR). Our Oracle-based PEPR data warehouse includes a novel time series query analysis tool (SGQT), enabling dynamic generation of graphs and spreadsheets showing the action of any transcript of interest over time. In this report, we demonstrate the utility of this tool using a 27 time point, in vivo muscle regeneration series. This data warehouse and associated analysis tools provides access to multidimensional microarray data through web-based interfaces, both for download of all types of raw data for independent analysis, and also for straightforward gene-based queries. Planned implementations of PEPR will include web-based remote entry of projects adhering to quality control and standard operating procedure (QC/SOP) criteria, and automated output of alternative probe set algorithms for each project (see
PMCID: PMC308738  PMID: 14681485
3.  Studies on the Regulation of Secretion in Clara Cells with Evidence for Chemical Nonautonomic Mediation of the Secretory Response to Increased Ventilation in Rat Lungs 
Journal of Clinical Investigation  1982;70(3):608-613.
Using electron microscopy and morphometric methods to assess secretion, we previously found that two times tidal volume ventilation of isolated perfused rat lung stimulates secretion by bronchiolar Clara cells; this effect is not prevented by β-adrenergic blockade (J. Clin. Invest. 1981. 67: 345-351.). In this study we used the isolated perfused rat lung and the anesthetized mechanically ventilated rat, to further study the mechanism by which large tidal volumes stimulate secretion by Clara cells. With the perfused lung we found (a) α-adrenergic inhibition did not block the secretory effect of ventilation at two times normal tidal volume; (b) indomethacin completely blocked the secretory action of two times tidal volume ventilation; (c) medium previously used to perfuse lungs ventilated at two times tidal volume, but not medium previously used to ventilate lungs at normal tidal volume, stimulated secretion by Clara cells when used to perfuse fresh lungs ventilated at tidal volume; (d) addition of prostacyclin to the fresh perfusate increased secretion by Clara cells of lungs ventilated at normal tidal volume. In anesthetized mechanically ventilated rats, sighs stimulated secretion by Clara cells; this increased secretion was inhibited by indomethacin but not by cholinergic blockade (bilateral vagotomy). These studies indicate that increased volume ventilation stimulates secretion by Clara cells in vivo and in vitro; they provide evidence that chemical nonadrenergic, noncholinergic mechanisms are involved in this secretion, and that prostaglandins may be the chemical messenger coupling the mechanico-secretory events.
PMCID: PMC370262  PMID: 7050173
4.  Changes in Sedimentation of Surfactant in Ventilated Excised Rat Lungs 
Journal of Clinical Investigation  1979;64(2):600-608.
We ventilated excised rat lungs at a constant tidal volume (CTV); they developed areas of atelectasis which could be reversed by a large inflation (CTV + I) or prevented by the addition of positive end-expiratory pressure to the CTV. To explore the possibility that these modes of ventilation led to changes in surfactant, we lavaged the lungs and centrifuged the returns at 500 g; we measured the amount of disaturated phosphatidylcholine (DSPC) in the resultant pellet and supernatant fluid as a marker for surfactant. We found 16.9±1.5 (mean±SE), 38.0±2.4, 18.3±1.6, and 21.7±2.3% of the total lavage DSPC, in the pellet from freshly excised, CTV, CTV + I, and positive end-expiratory pressure to the CTV lungs, respectively. The total amount of lavage DSPC was the same in all groups.
The ultrastructure of acellular material pelleted by sequential centrifugation of lavage returns at 500, 1,000, and 60,000 g was examined. We found mostly tubular myelin in the 500-g and 1,000-g pellets, but no tubular myelin in the 60,000-g pellet.
Air inflation pressure-volume measurements from the degassed state revealed that the opening pressure and recoil pressures up to 75% of total lung capacity were significantly higher in the CTV than in the CTV + I lungs. There were no differences between these groups in air deflation or in saline inflation and deflation pressure-volume measurements. Our findings suggest that CTV leads to increases in the tubular myelin form of surfactant and that this leads to increased surface tension in alveoli which results in alveolar collapse.
PMCID: PMC372156  PMID: 379047
The Journal of Cell Biology  1973;59(1):246-250.
PMCID: PMC2110922  PMID: 4752408
6.  Adaption to Hyperoxia 
Journal of Clinical Investigation  1974;53(3):705-709.
We studied the influence of prolonged exposure to hyperoxia (O2 > 98%) on protein synthesis and on the ultrastructure of the granular pneumocyte. To study protein synthesis, as indicated by l-[U-14C]-leucine incorporation into protein, lung slices were incubated with radioactive leucine and a surface-active fraction was obtained by ultracentrifugation of lung homogenates. We found that, following an initial depression in protein synthesis after 48 h of hyperoxia, protein synthesis in rats exposed to oxygen for 96 h rose to greater than control levels. This increase in protein synthesis was noted in whole lung protein and in protein present in the surface-active fraction.
Stereologic ultrastructural analysis of granular pneumocytes revealed that the lamellar bodies occupy the same percentage of cytoplasmic volume in oxygen-exposed and control rats after 96 h; a previous study had shown lamellar bodies of oxygen-exposed rats to occupy less volume than those of control rats after 48 h of exposure at which time protein synthesis was also depressed. After 96 h of exposure there is a greater amount of rough endoplasmic reticulum in the granular pneumocytes of oxygen-exposed rats.
These studies show that after 96 h of hyperoxia the lung has recovered its ability to synthesize protein including protein in the surface-active fraction and that these biochemical changes are associated with consistent ultrastructural alterations in the granular pneumocyte.
PMCID: PMC333050  PMID: 4405905
7.  Hyperoxia: A Stereologic Ultrastructural Examination of Its Influence on Cytoplasmic Components of the Pulmonary Granular Pneumocyte 
Journal of Clinical Investigation  1973;52(3):566-570.
We used the technique of lineal analysis to study the influence of 48 h of hyperoxia on cytoplasmic organelles of pulmonary granular pneumocytes with particular reference to their lamellar bodies. We undertook this study because lamellar bodies are considered to be storage granules for pulmonary surfactant and because we had found that hyperoxia decreased [14C]leucine incorporation into protein of a surface-active lung fraction.
We found that for lamellar bodies the percent cytoplasmic volume was 12.8±1.5 (mean±SEM) and 8.4±2.2, the organelle area (μm2) per organelle was 0.98±0.13 and 0.62±0.10 and the organelle volume (μm2) was 0.35±0.04 and 0.18±0.01, for air- and oxygen-exposed rats, respectively, (P=<0.05). The surface density of the lamellar body membrane was 7.05±0.47 and 9.36±0.96 (P=<0.05) for air- and oxygen-exposed rats. There were no differences in lamellar body number per cytoplasmic area or per pneumocyte between air- and oxygen-exposed rats. There were no statistical differences in these parameters between mitochondria of air- or oxygen-exposed rats. The surface density of the rough endoplasmic reticulum was the same in both groups.
This study indicates that granular pneumocytes of rats exposed to hyperoxia have the same number of lamellar bodies as control rats but the lamellar bodies are smaller. This findings in consistent with the hypothesis that the hyperoxia-induced decrease in protein synthesis by lung represents at least in part a decreased synthesis of the secretory lipoprotein-pulmonary surfactant.
PMCID: PMC302294  PMID: 4685081
8.  Hyperoxia: Influence on Lung Mechanics and Protein Synthesis 
Journal of Clinical Investigation  1973;52(3):559-565.
We studied the time-course of the influence of in vivo hyperoxia on lung mechanics and on protein synthesis. After 24 h of exposure to greater than 98% O2 at 1 atm there were no alterations in descending pressure-volume curves (air or saline) of lungs excised from O2-exposed rats compared to control rats. After 48 h of hyperoxia there was a decrease in lung compliance.
To study protein synthesis, as indicated by L-[U-24C] leucine incorporation into protein, lung slices were incubated with L-[U-14C]leucine and surface-active material then obtained by ultracentrifugation of lung homogenates. We measured radioactivity in total protein and in protein in the surface-active fraction. There were no alterations in incorporation after 12 h of hypertoxia. After 24 h of hyperoxia there were significant decreases (P<0.05) in L-[U-14C]leucine incorporation into total protein and into protein of the surface-active fraction. After 48 h of hyperoxia incorporation into protein of the surface-active fraction was decreased to a greater extent than incorporation into total protein, 63±4% and 75±5%, respectively, (P<0.025).
These studies show that hyperoxia produces a major decrease in protein synthesis, including synthesis of protein in a surface-active fraction, before the onset of any detectable changes in the static compliance of excised lungs.
PMCID: PMC302293  PMID: 4739291
9.  Alveolar cells: incorporation of carbohydrate into protein and evidence for intracellular protein transport 
Journal of Clinical Investigation  1968;47(2):366-374.
Alveolar cells incubated with radioactive glucosamine, galactose, and mannose incorporate radioactivity into protein, that is, into material insoluble in cold and hot trichloroacetic acid and not extracted by lipid solvents. This incorporation is incompletely inhibited by puromycin hydrochloride. The kinetics of the subcellular distribution of radioactivity are consistent with a precursor-product relationship between microsomal protein and the protein of particles sedimenting at 15,000 g. It is thus suggested that alveolar cells incorporate these substrates intact into protein at the microsomal level with subsequent transfer of this newly formed material to particles sedimenting at 15,000 g.
PMCID: PMC297179  PMID: 12066780

Results 1-11 (11)