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Biomedical subjects

J A Last

Publications and source records attributed to J A Last.

At least 55 records · Page 3Linked to original sources
PubMed1991

Global atmospheric change: potential health effects of acid aerosol and oxidant gas mixtures.

Inhalation toxicology experiments in whole animals have demonstrated a remarkable lack of toxicity of sulfuric acid in the form of respirable aerosols, especially in rats and nonhuman primates. Thus, much of the current experimental emphasis has shifted to the evaluation of the potential health effects of acid aerosols as components of mixtures. Rats have been concurrently exposed to mixtures of ozone or nitrogen dioxide with respirable-sized aerosols of sulfuric acid, ammonium sulfate, or sodium chloride, or to each pollutant individually. Their responses to such exposures have been evaluated by various quantitative biochemical analysis of lung tissue or wash fluids ("lavage fluid") or by quantitative morphological methods ("morphometry"). Such studies have mainly been performed in the acute time frame due to the inherent limitations of the most sensitive assays available and have generally involved exposures for 1 to 9 days, depending on the assays used. Good correlations were found between the most sensitive biochemical indicators of lung damage (protein content of lung lavage fluid or whole lung tissue and lung collagen synthesis rate) and the exposure concentration of oxidant gas present alone or in mixtures with acidic aerosols showing interactive effects. Synergistic interaction between ozone and sulfuric acid aerosol was demonstrated to occur at environmentally relevant concentrations of both pollutants by several of the analytical methods used in this study. Such interactions were demonstrated at concentrations of ozone as low as 0.12 ppm and of sulfuric acid aerosol at concentrations as low as 5 to 20 micrograms/m3.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed1991

Synergistic effects of air pollutants: ozone plus a respirable aerosol.

Rats were concurrently exposed to mixtures of ozone or nitrogen dioxide and respirable-sized aerosols of sulfuric acid, ammonium sulfate, or sodium chloride, or to each pollutant individually. Their responses to such exposures were evaluated by various quantitative biochemical analyses of lung tissue or lavage fluids, or by morphometric analyses. Such studies were performed in the acute time frame, generally involving exposures of from one to nine days, depending on the assays used. Correlations between the biochemical and morphometric results were examined over a wide range of pollutant concentrations in the exposure chambers. Good correlations were found between the most sensitive biochemical indicators of lung damage--the protein content of lung lavage fluid or whole lung tissue and the rate of lung collagen synthesis--and the morphometric estimation of volume density or volume percent of the centriacinar lung lesion characteristically observed in animals exposed to ozone. Synergistic interaction between ozone and sulfuric acid aerosol was demonstrated to occur at environmentally relevant concentrations of both pollutants by several of the analytical methods used. Such interactions were demonstrated at concentrations of ozone as low as 0.12 parts per million (ppm)2 and of sulfuric acid aerosol at concentrations as low as 5 to 20 micrograms/m3. The acidity of the aerosol is a necessary (and apparently a sufficient) condition for such a synergistic interaction between an oxidant gas and a respirable aerosol to occur. A hitherto unexpected synergistic interaction between nitrogen dioxide and sodium chloride aerosol was found during these studies; it is hypothesized that this was due to formation of their acidic (anhydride) reaction product, nitrosyl chloride, in the chambers during exposure to the mixture. Preliminary experiments treating exposed animals in vivo with various free-radical scavengers suggested that dimethylthiourea, a hydroxyl-radical scavenger, might be protective against effects of ozone on rat lungs. This observation might have mechanistic implications, but further studies will be necessary to determine the significance of these findings.

Aerosols↗
PubMed1990

Collagen cross-linking in adult patients with acute and chronic fibrotic lung disease. Molecular markers for fibrotic collagen.

Lung tissue from patients with interstitial lung disease (ILD), adult respiratory distress syndrome (ARDS), and control subjects with no obvious fibrotic lung disease was analyzed for its content of the collagen cross-links hydroxylysinonorleucine (HLNL), dihydroxylysinonorleucine (DHLNL), and hydroxypyridinium (OHP). We observed significant elevations of the DHLNL:HLNL ratio in patients with ARDS, and significant increases in the content of OHP in lungs of patients with ILD. These results are consistent with data from animal models of fibrotic lung disease, suggesting that increases in the DHLNL:HLNL ratio of lung collagen may serve as a marker of an acute fibrotic episode, whereas increased lung collagen OHP content serves as a marker of chronic lung fibrosis. We suggest that the underlying mechanism for the changes in DHLNL content in (pre)fibrotic acutely injured lung tissue and in OHP content in long-term fibrosis may be an increase in the activity of lysyl hydroxylase, a key intracellular enzyme responsible for a specific post-translational modification of collagen.

Acute Disease↗
PubMed1990

Hydroxylation of collagen by lungs of rats administered bleomycin.

Collagen synthesized by tissue minces from lungs of rats administered 1 unit of bleomycin by intratracheal instillation 1 or 2 wk earlier contained relatively more hydroxylysine than did collagen made by lungs from saline-instilled control animals. Most, if not all, of the relative increase in lysine hydroxylation could be localized to the alpha 1 (I) chain of type I collagen. Lung homogenates from bleomycin-treated rats showed increased activity of lysyl hydroxylase (EC 1.14.11.4), the enzyme catalyzing the conversion of collagen-bound lysine to hydroxylysine. Thus, the increased hydroxylation of lysine and of lysine-derived cross-links previously observed in collagen of diseased human lungs and in animal models of lung fibrosis is reflected in an in vitro system.

Animals↗
PubMed1990

Expression of mucin synthesis and secretion in human tracheobronchial epithelial cells grown in culture.

The effects of culture conditions on growth and differentiation of human tracheobronchial epithelial (HTBE) cells have been defined. Epithelial cells were dissociated from tissues by protease treatment and were plated on tissue culture dishes in F12 medium supplemented with insulin, transferrin, epidermal growth factor, hydrocortisone, cholera toxin, bovine hypothalamus extract, and retinol. HTBE cells did not express any mucociliary function (ciliogenesis or mucin secretion) on tissue culture plastic, but they could be passaged 3 to 5 times with a total of 10 to 25 population doublings. Cells from early passages re-express both these functions when transplanted to tracheal grafts. When tissue culture plates were coated with collagen film or collagen gel substrata, cell attachment and proliferation were stimulated. However, the expression of mucous cell function in culture occurred only when cells were plated on collagen gel substrata and vitamin A (retinol) was present in the medium. Mucous cell differentiation under optimal conditions was defined by ultrastructural studies, by immunologic studies with mucin-specific monoclonal antibodies, and by carbohydrate and amino acid compositional analyses of mucin-like glycoproteins purified from culture medium. These results demonstrate for the first time that HTBE cells can express mucin synthesis and secretion under appropriate culture conditions.

Amino Acids↗
PubMed1989

Biosynthesis of collagen crosslinks. II. In vivo labelling and stability of lung collagen in rats.

Rat lung collagen was labelled in vivo by a single intraperitoneal injection of [3H]lysine at several key timepoints in lung development: days 11 (alveolar proliferation), 26 (start of equilibrated growth), 42 (end of equilibrated growth), and 100 (adult lung structure present). The rates of deposition of labelled hydroxylysine and the difunctional, Schiff base-derived crosslinks hydroxylysinonorleucine (HLNL) and dihydroxylysinonorleucine (DHLNL) were quantified. We also measured total lung content of the trifunctional, mature crosslink hydroxypyridinium (OHP) in these same animals. While the relative rates of accumulation of labelled collagen [3H]hydroxylysine differed by a factor of about 6 at the different times of injection of labelled precursor, quantitative and qualitative patterns of collagen crosslinking were very similar at all of the lung developmental stages studied. Furthermore, there was little or no breakdown of the lung collagen pool as defined by the presence of labelled crosslinks; changes in lung DHLNL content could be completely accounted for by its maturation to OHP, regardless of the age of the rats when injected with the radioactive precursor. We conclude that mature, crosslinked collagen in the lungs of rats, which is obligatorily an extracellular pool, is not being degraded at a measurable rate. Therefore, studies of others that have shown apparent high rates of breakdown of newly synthesized collagen in lungs of whole animals using different methods are probably not reflective of the metabolic fate of total lung collagen, and may indicate that degradation of normal lung collagen occurs predominantly or exclusively intracellularly.

Animals↗
PubMed1989

Biosynthesis of collagen crosslinks. III. In vivo labeling and stability of lung collagen in rats with bleomycin-induced pulmonary fibrosis.

Rats were injected intraperitoneally with 1 mCi (each) of [3H]lysine at Day 11 of neonatal life to label their lung collagen. Five weeks later, half of the animals were given an intratracheal injection of 1.5 U of bleomycin sulfate via a tracheostomy; control animals received saline intratracheally by the same technique. Age-matched groups of control and bleomycin-treated rats were killed, and their lung collagen was analyzed at zero (control animals only), 1, 2, 4, 6, and 10 wk after bleomycin administration, a time course appropriate for development of pulmonary fibrosis in this animal model. We measured radioactivity in hydroxylysine and in the difunctional collagen crosslinks hydroxylysinonorleucine and dihydroxylysinonorleucine at each time point. No evidence of breakdown of this pool of mature, preformed collagen was observed in lungs of either the control or the bleomycin-treated rats. We also measured the total lung content of hydroxypyridinium, a trifunctional collagen crosslink, by its intrinsic fluorescence. There was no evidence of collagen degradation in lungs of either group of rats by this criterion either. We conclude that there is no biochemically detectable turnover of mature lung collagen, defined as that pool of lung collagen that is obligatorily extracellular (i.e., crosslinked and containing labeled hydroxylysine from an injection of precursor 5 to 15 wk earlier), in either normal rat lungs or lungs of rats made fibrotic with bleomycin. Statistical analysis of the data suggests that our methodology was sensitive and precise enough to have detected turnover of less than 0.5% of lung collagen per day, some 20-fold less than estimates of lung collagen turnover that have been suggested to be occurring in vivo by others using different techniques and presumably studying different pools of lung collagen.

Animals↗
PubMed1989

Effects of inhaled acids on lung biochemistry.

Effects of respirable aerosols of sulfuric acid, ammonium sulfate, sodium sulfite, and ammonium persulfate on lungs of rats are reviewed. The literature regarding interactions between ozone or nitrogen dioxide and acidic aerosols (ammonium sulfate, sulfuric acid) is discussed. An unexpected interaction between nitrogen dioxide and sodium chloride aerosol is also discussed. An attempt is made to identify bases for prediction of how and when acid aerosols might potentiate effects of inhaled gases.

Acid Rain↗
PubMed1988

Synergistic interaction of ozone and respirable aerosols on rat lungs. IV. Protection by quenchers of reactive oxygen species.

In previous studies we have shown interactions between ozone and acidic respirable aerosols as evaluated by sensitive biochemical and quantitative morphological endpoints. In the present paper we have attempted to test the hypothesis that active oxygen species might play a role in lung damage caused by ozone +/- sulfuric acid aerosol. Rats were administered various scavengers of active oxygen species via the intraperitoneal (i.p.) route before and during exposure to 0.12, 0.20, or 0.64 ppm of ozone +/- 0.04, 0.1, 0.2, 0.5, or 1.0 mg/m3 of sulfuric acid aerosol. Vitamin E, a lipid-soluble free radical scavenger, beta-carotene (the precursor of vitamin A), a singlet oxygen scavenger, and dimethylthiourea, a hydrogen peroxide scavenger, were tested. Dimethylthiourea at doses of 50-500 mg/kg per day was able to protect rats from the effects of ozone, suggesting a role for hydrogen peroxide in ozone-induced lung damage in vivo. Neither vitamin E nor beta-carotene at 100 mg/kg doses had any protective activity in our experiments, despite documentation of increased lung content of the scavengers in animals receiving these agents. These results suggest that water solubility may play a role in the efficacy of the scavenging agents under our exposure protocols. We conclude that: (1) hydrogen peroxide may be involved in ozone-induced lung damage; and (2) that lung injury by ozone and by ozone + sulfuric acid aerosol may share common pathways.

Aerosols↗
PubMed1988

Comparison of daily and seasonal exposures of young monkeys to ozone.

Oxidant air pollution tends to occur in both seasonal and daily cycles of polluted and clean air. To compare the effects of these 2 cycles, we exposed 2 groups of 7-month-old male monkeys to 0.25 ppm (0.49 mg/m3) of ozone (UV photometric standard) 8 h/day either daily or, in the seasonal model, days of alternate months during a total exposure period of 18 months. This is a longer ozone exposure period than any previously reported. A control group breathed only filtered air. Young monkeys were studied as their lungs are similar to those of man and their lungs, like those of man, grow over a period of several years. Monkeys from the seasonal exposure model, but not those exposed daily, had significantly increased total lung collagen content, chest wall compliance, and inspiratory capacity. All monkeys exposed to ozone had respiratory bronchiolitis with significant increases in related morphometric parameters. The only significant difference between seasonal and daily groups was in the volume fraction of macrophages. Even though the seasonally exposed monkeys were exposed to the same concentration of ozone for only half as many days, they had larger biochemical and physiological alterations and equivalent morphometric changes as those exposed daily. Lung growth was not completely normal in either exposed group. Long-term effects of oxidant air pollutants which have a seasonal occurrence may be more dependent upon the sequence of polluted and clean air than on the total number of days of pollution. Estimations of the risks of human exposure to seasonal air pollutants from effects observed in animals exposed daily may underestimate long-term pulmonary damage.

Air Pollutants↗
PubMed1987

Analysis of age-associated changes in collagen crosslinking in the skin and lung in monkeys and rats.

The present study was designed to address a specific question: can we define collagen aging in vivo in terms of alterations in collagen crosslinking? In order to assess the complete spectrum of change throughout life, tissues from rats, monkeys and (where available) humans were examined at ages ranging from fetal to old. Skin and lung were selected in order to include all of the crosslinks derived from lysyl oxidase-generated aldehydes that have been identified thus far, both reducible and nonreducible. Crosslinks analyzed included hydroxylysinonorleucine, dihydroxylysinorleucine, histidinohydroxymerodesmosine, hydroxypyridinium, lysyl pyridinium, and a deoxy analogue of hydroxypyridinium found in skin that differs structurally from lysyl pyridinium. Tissues from both a short-lived species (rats) and a long-lived species (monkeys) were analyzed to test further the hypothesis that changes in crosslinking are linked predominantly to biological age of the animal, rather than temporal aging. We found that biological aging seems to regulate certain predictable changes during the first part of the lifespan: the disappearance postnatally of dihydroxylysinonorleucine in skin, the rapid decrease in difunctional crosslink content in lung and skin during early growth and development, and the gradual rise in hydroxypyridinium and lysyl pyridinium in lung tissue. Changes in crosslinking were far less predictable during the second half of the lifespan. Although hydroxypridinium content continued to rise or reached a plateau in rat and monkey lungs, respectively, it showed a decrease in human lungs. The analogous trifunctional crosslink in skin, the so-called 'pyridinoline analogue', decreased dramatically in both rats and monkeys in later life. Our data suggest that caution must be taken in drawing inferences about human connective tissue aging from experiments performed in short-lived species such as rodents. Furthermore, the finding that there may be fewer total lysyl oxidase-derived crosslinks per collagen molecule in very old animals as compared with young animals suggests that we may need to expand our concepts of collagen crosslinking.

Aging↗
PubMed1987

Effects of ozone on lung and somatic growth. Pair fed rats after ozone exposure and recovery periods.

Minor differences in lung growth and development during childhood have been considered as a potential cause of rapid decline in pulmonary function in adulthood. Inhalation of ozone commonly causes changes in both body weight and lung volumes, which complicates interpretation of any changes in lung growth. The effects of ozone on lung growth were studied in rats which were pair fed. This technique permitted comparison of ozone-exposed and filtered-air control rats of the same body weight and body size as well as age and sex. Exposure was to filtered air or to 0.64 or 0.96 ppm ozone (UV standard) 8 h/night for 42 nights. A second control group was fed ad libitum and exposed to only filtered air. Half the rats were studied at the end of the 42-night exposures, the rest after a 42-day post-exposure period during which all rats were fed ab libitum and breathed filtered air. Rats examined at the end of the exposure period had larger saline and fixed lung volumes. These larger lungs had greater volumes of parenchyma, alveoli and respiratory bronchioles. Some of these changes persisted throughout a 42-day post-exposure period. Ozone inhalation by young rats alters lung growth and development in ways likely to be detrimental and those changes persist after ozone inhalation stops.

Animals↗
PubMed1987

Synergistic interaction of ozone and respirable aerosols on rat lungs. III. Ozone and sulfuric acid aerosol.

Previously we have demonstrated that a synergistic interaction, as evaluated by several biochemical, toxicological, and morphological responses of the lung, results from exposure of rats to ozone (O3) in conjunction with moderate concentrations of acidic, but not neutral, aerosols. To extend these studies, groups of rats were continuously exposed to either O3 or sulfuric acid aerosol alone, or to combinations of these pollutants. Pulmonary responses from these rats were measured by assay, after exposures for 6 hr to 7 days, of total lavageable protein content, total lung tissue protein content after 5, 7, or 9 days of exposure, or apparent collagen synthesis rates from lung tissue after 7 days of exposure. While the lavageable protein content from rats exposed for 3 days to 0.1 or 1.0 mg/m3 of sulfuric acid aerosol alone was not different from control values, significant elevations from control values were observed from groups exposed to 0.12, 0.20, or 0.64 ppm of O3. Synergy was demonstrated by this assay upon exposure of rats to 0.20 ppm of O3 in conjunction with 0.1, 0.5, or 1.0 mg/m3 of sulfuric acid aerosol. Similarly, the tissue protein content from rats exposed to 0.1 or 1.0 mg/m3 of sulfuric acid aerosol alone was indistinguishable from control values. Significant elevations from control values were observed by this assay from groups of rats exposed to 0.64 or 0.20 ppm of O3, and a synergistic interaction was demonstrated between 0.64 ppm of O3 and 1.0 mg/m3 of sulfuric acid aerosol. Furthermore, synergy was observed by quantification of increased total lung protein between 0.20 ppm of O3 + 40 micrograms/m3 and higher concentrations of sulfuric acid aerosol. Values of the lung collagen synthesis rate from rats exposed to 0.1, but not 1.0, 0.5, or 0.04 mg/m3 of sulfuric acid aerosol were significantly higher than values from lungs of control animals. Significant elevations from control values were also observed by this assay from groups of rats exposed to 0.64 or 0.20 ppm of O3. A synergistic interaction was demonstrated by the collagen synthesis rate assay between groups of rats exposed to 0.64 ppm of O3 + 0.20 mg/m3 and higher concentrations of sulfuric acid aerosol or between groups exposed to 0.20 ppm of O3 + 40 micrograms/m3 and higher concentrations of sulfuric acid aerosol. These results demonstrate synergy between O3 and sulfuric acid aerosol upon exposure to concentrations of each pollutant at or near peak hourly ambient levels in polluted urban atmospheres.

Aerosols↗
PubMed1987

Long-term consequences of exposure to ozone. II. Structural alterations in lung collagen of monkeys.

The effects of chronic exposure to ozone on lung collagen crosslinking were investigated in two groups of juvenile cynomolgus monkeys exposed to 0.61 ppm of ozone 8 hrs per day for 1 year. One group was killed immediately after the exposure period; the second exposed group breathed filtered air for 6 months after the ozone exposure before being killed. Previous studies of these monkeys had revealed that lung collagen content was increased in both exposed groups (J.A. Last et al., (1984). Toxicol. Appl. Pharmacol. 72, 111-118). In the present study specific collagen crosslinks were quantified in order to determine whether the excess collagen in the lungs of these animals was structurally normal or abnormal. In the group killed immediately after exposure, the difunctional crosslink dehydrodihydroxylysinonorleucine (DHLNL) was elevated, as was the ratio of DHLNL to dehydrohydroxylysinonorleucine (HLNL). Lung content of the mature nonreducible crosslink hydroxypyridinium was also increased in this group. In the group killed after a 6-month postexposure period, lung content of the difunctional crosslinks DHLNL and HLNL was indistinguishable from control values. However, lung hydroxypyridinium content was significantly increased. The changes in collagen crosslinking observed in the group killed at the termination of exposure are characteristic of those seen in lung tissue in the acute stage of experimental pulmonary fibrosis. The changes seen in the postexposure group suggest that while the lung collagen being synthesized at the time the animals were killed was apparently normal, "abnormal" collagen synthesized during the period of ozone exposure was irreversibly deposited in the lungs. This study suggests that long-term exposure to relatively low levels of ozone may cause irreversible changes in lung collagen structure.

Animals↗
PubMed1987

Synergistic interaction between nitrogen dioxide and respirable aerosols of sulfuric acid or sodium chloride on rat lungs.

We examined interactions in rats between NO2 gas and respirable aerosols of sulfuric acid (H2SO4) or sodium chloride (NaCl). Rats were exposed for 1, 3, or 7 days to 5 ppm of NO2 gas, alone or in combination with 1 mg/m3 of H2SO4 or NaCl aerosols. The apparent rate of collagen synthesis by lung minces was measured after 7 days of exposure, and the protein content of whole lung lavage fluid was measured after 1 or 3 days of exposure. Responses from rats exposed to 5 ppm of NO2 alone were significantly different from controls by these assays. A synergistic interaction was demonstrated between 5 ppm of NO2 and 1 mg/m3 of either H2SO4 or NaCl aerosol as evaluated by measurement of the rate of lung collagen synthesis. A synergistic interaction was also demonstrated by the criterion of increased protein content of lung lavage fluid in rats exposed to 5 ppm of NO2 and 1 mg/m3 of H2SO4 aerosol after 1 day of exposure and between 5 ppm of NO2 and 1 mg/m3 of NaCl aerosol after 3 days of exposure. These observations with 5 ppm of NO2 alone and in combination with 1 mg/m3 of NaCl aerosol support the hypothesis that formation of nitrosyl chloride may contribute to a synergistic interaction between NO2 gas and NaCl aerosol. These results suggest that, in general, combinations of oxidant gases with respirable acidic aerosols or with acidogenic gases will demonstrate interactive effects on rat lungs. Such a hypothesis is testable and makes specific predictions about effects of inhalation of pollutant mixtures.

Acid Phosphatase↗
PubMed1987

A molecular marker for fibrotic collagen in lungs of infants with respiratory distress syndrome.

Lung samples from four infants who died of respiratory complications of prematurity (Infant Respiratory Distress Syndrome, IRDS) were analyzed for their content of various collagen crosslink amino acids by newly developed techniques of high-performance liquid chromatography. Comparable analyses were performed with tissue from stillborn infants with apparently normal lungs (control group) and from adults without apparent lung disease. We observed increased amounts of the difunctional crosslink dihydroxylysinonorleucine (DHLNL) in the IRDS lungs. Gestational age seemed to be the most important determinant of total lung content of the trifunctional crosslink hydroxypyridinium (OHP). Term infants had about one-third of the OHP content in their lung collagen as was found in the adult lungs. These observations suggest that there are important changes in the molecular structure of collagen in human fibrotic lung disease, changes that are paralleled in various animal models of experimental pulmonary fibrosis, and in various human diseases involving abnormalities of skin or bone collagen metabolism.

Adult↗