Search PubMed⌕ Search

Biomedical subjects

J S Kerr

Publications and source records attributed to J S Kerr.

At least 73 records · Page 4Linked to original sources
PubMed1987

Damage and repair of lung connective tissue in rats exposed to toxic levels of oxygen.

We studied damage and repair of lung connective tissue in rats exposed to toxic amounts of oxygen by measuring lung content of collagen and elastin and the number of collagen fragments in lung lavage fluid after exposure to 98% O2 for 60 h. Lung collagen was decreased 17%, and collagen fragments in lavage fluid were increased 4- to 5-fold in O2-exposed rats compared with those in control rats. No biochemical evidence of elastin degradation was found. Mild emphysematous changes and a leftward shift of fluid-filled, pressure-volume curves were induced within 2 wk after recovery from exposure to O2. Administration of the lathyrogen beta-aminopropionitrile worsened the emphysematous lesion produced by hyperoxia, suggesting that replacement of connective tissue during repair limits the extent of emphysema. We conclude that lung collagen is degraded and an emphysematous lesion is produced by relatively short exposure to toxic amounts of oxygen.

Aging↗
PubMed1987

Degradation of collagen in lung tissue slices exposed to hyperoxia.

Exposure of animals to oxidant gases produces a mild emphysema, and O2-derived free radicals are capable of degrading connective tissues in vitro. It is postulated that degradation of connective tissue by O2-derived free radicals leads to emphysema in these models. To determine whether exposure of lung tissue slices to an oxidant gas results in degradation of collagen and to investigate factors mediating this degradation, we exposed lung tissue slices from normal rats to hyperoxia (95% O2, 5% CO2) and measured hydroxyproline release into the medium. After a 4-h exposure, the hydroxyproline released was 5.3 +/- 0.2 micrograms/g lung tissue (n = 10) in normoxia and 8.1 +/- 0.6 micrograms/g tissue (n = 13) in hyperoxia (p less than 0.05), suggesting degradation of collagen. The addition of 0.1% trypsin to the initial incubation medium caused a synergistic increase in hydroxyproline release from O2-exposed slices: normoxia/trypsin, 46.2 +/- 3.6 micrograms/g tissue (n = 10); hyperoxia/trypsin, 61.4 +/- 3.6 micrograms/g tissue (n = 11) (p less than 0.05). The addition of proteinase inhibitors completely suppressed the O2-induced release of hydroxyproline, suggesting that proteolytic enzymes are involved in hyperoxia-mediated degradation of lung collagen.

Animals↗
PubMed1986

C1q content of serum and lung lavage fluid of rats exposed to toxic levels of oxygen.

We used a sensitive hemolytic assay to measure the level of C1q, a subcomponent of the first complement protein in the classic pathway, in bronchoalveolar lavage fluid and serum of rats exposed to air and hyperoxia. The serum level was 125 +/- 5 micrograms/ml and the lavage level was 41 +/- 17 ng/ml in rats breathing air. In rats exposed to acute oxygen toxicity (95% O2 for 66 hr), the serum level was at 107 +/- 10 micrograms/ml, but the level in lavage fluid increased to 2457 +/- 400 ng/ml (p less than 0.05 compared to air). Administration of the proline analogue cis-4-hydroxy-L-proline to air- and O2-exposed rats reduced the serum C1q level by 28% and 34%, respectively (both p less than 0.05), presumably by interfering with metabolism of the collagen-like sequence of C1q. The level of C1q in bronchoalveolar lavage fluid is a sensitive marker of acute lung injury.

Animals↗
PubMed1985

Nutritional emphysema in the rat. Influence of protein depletion and impaired lung growth.

Emphysema is produced by severe food restriction in rats and is postulated to result from depletion of lung connective tissue. We studied (1) whether total dietary protein depletion worsens nutritional emphysema, and (2) whether the reduced content of lung connective tissue in nutritional emphysema results from lack of accumulation caused by impaired lung growth or by a net loss from the lung. Lewis rats weighing 200 g were restricted to one third food intake with or without protein for 6 wk. Lungs were assessed by morphometry, pressure-volume (P-V) measurements, and content of collagen and elastin. Emphysema was found by morphometry (but not by P-V measurements) in food-restricted rats, and contrary to expectation, emphysema was less severe in those depleted of protein. Collagen and elastin content were reduced in emphysematous lungs; however, the levels were not below those found prior to nutritional intervention, suggesting that lack of growth, not depletion, accounts for the reduced content.

Animals↗
PubMed1985

Rat Clq: isolation and purification from normal serum and development of a sensitive hemolytic assay.

Rat Clq was isolated and purified from normal rat serum by a two-step procedure: affinity chromatography on a human IgG-Sepharose 4B column and Bio-Gel A 5m column chromatography. From 1.8 l of normal serum, the procedure yielded 4.5 mg of homogeneous and hemolytically active rat Clq as shown by three bands of peptide in SDS polyacrylamide gel electrophoresis under reducing conditions and by a single precipitin line between rat Clq and rabbit anti-rat Clq antibody. Rabbit anti-rat Clq antibody prepared by immunizing a rabbit with 225 micrograms of rat Clq was specific as shown by a single precipitin line between the antibody and normal rat serum and rat Clq with complete identity. The amino acid composition of rat Clq was very similar to that of human Clq. The purification procedure also yielded Clq-depleted rat serum which was used with the homogeneous Clq to establish a sensitive hemolytic assay: 4.5-13.5 ng of rat Clq can be reproducibly quantitated. The concentration of Clq in Brown Norway rats was estimated to be 41.5 +/- 3.0 micrograms/ml serum.

Amino Acids↗
PubMed1984

Effect of proline analogs on oxygen toxicity-induced pulmonary fibrosis in the rat.

Proline analogs inhibit collagen biosynthesis and prevent accumulation of collagen in tissues. The antifibrotic effects of three proline analogs, cis-hydroxyproline, L-azetidine-2-carboxylic acid, and L-3,4-dehydroproline, were compared in a rat oxygen toxicity model. The specificity of these agents for collagen was examined by measuring their effects on noncollagen protein and elastin accumulation in the lung. Increased lung collagen was produced by exposing rats to 95% O2 for 60 hr followed by a 2-week recovery period. Animals were treated with the proline analogs for the 2-week period. Oxygen exposure in untreated animals increased lung collagen 26% above air-breathing controls, and this increase was prevented by all three analogs. Increased noncollagen protein was also prevented by these agents, suggesting they were not entirely specific for collagen. Elastin accumulation, however, was not inhibited by cis-hydroxyproline. It was concluded that proline analogs were antifibrotic, but affected the metabolism of noncollagen protein.

Animals↗
PubMed1984

Reduction of chronic hypoxic pulmonary hypertension in the rat by beta-aminopropionitrile.

We administered antifibrotic agent beta-aminopropionitrile (BAPN) to rats exposed to 10% O2-90% N2 for 3 wk to prevent excess vascular collagen accumulation. Groups of Sprague-Dawley rats studied were air breathing, hypoxic, and hypoxic treated with BAPN, 150 mg/kg twice daily intraperitoneally. After the 3-wk period, we measured mean right ventricular pressure (RVP), the ratio of weight of right ventricle to left ventricle plus septum (RV/LV + S), and hydroxyproline content of the main pulmonary artery (PA) trunk. Hypoxia increased RVP from 14 to 29 mmHg; RVP was 21 mmHg in hypoxic BAPN-treated animals. Hypoxia increased the RV/LV + S ratio from 0.28 to 0.41; the ratio was 0.32 in hypoxic BAPN-treated animals. Hypoxia increased PA hydroxyproline from 20 to 239 micrograms/artery; hydroxyproline was 179 micrograms/artery in hypoxic BAPN-treated animals. Thus BAPN prevented pulmonary hypertension, right ventricular hypertrophy, and excess vascular collagen produced by hypoxia. We conclude that vascular collagen contributes to the maintenance of chronic hypoxic pulmonary hypertension.

Aminopropionitrile↗
PubMed1982

2-Deoxy-D-glucose uptake by rat granular pneumocytes in primary culture.

Uptake of 2-deoxy-D-glucose (DG) was investigated with rat granular pneumocytes isolated in primary culture. Cells attached to flasks were incubated in Minimal Essential Medium usually containing 5 mM DG in place of glucose. Uptake of DG increased progressively with time of incubation and approached a plateau value of 35-40 mumol/10(6) cells at 60 min. Uptake increased as a function of external DG concentration with half-maximal uptake at approximately 2.0 mM DG. DG uptake was inhibited by the presence of glucose, alpha-methylglucoside, phlorizin, ouabain, or sodium-free medium. After 60 min incubation, approximately 20% of total intracellular DG was in the free form, and the calculated mean intracellular concentration of free DG (n = 4) was approximately twice the external concentration. Phosphatase activity was indicated by increase in free DG and efflux from cells after removal of external DG. In comparison with pneumocytes, uptake of DG by alveolar macrophages showed different kinetics, and intracellular free DG did not exceed the extracellular concentration. These findings indicate that type II cells take up DG by a sodium-dependent, carrier-mediated transport process that results in accumulation of free sugar against a concentration gradient.

Adenosine Triphosphate↗
PubMed1982

beta-Aminopropionitrile prevents bleomycin-induced pulmonary fibrosis in the hamster.

beta-Aminopropionitrile (beta APN), an agent that prevents collagen accumulation in tissues, was evaluated for its ability to prevent excess collagen formation in bleomycin-induced pulmonary fibrosis in the hamster. Two groups of animals received a single endotracheal dose of bleomycin; one of these was injected with beta APN twice daily for 30 days. A third group received endotracheal saline and a fourth group received saline and beta APN. After 30 days, we measured pressure-volume curves of saline-filled lungs, collagen content, and degree of fibrosis. Endotracheal bleomycin increased collagen content, decreased lung volume, and produced fibrosis and a mortality rate of 51%. The administration of beta APN to bleomycin-treated animals prevented excess collagen accumulation and diminished total protein, reversed volume diminution, produced less fibrosis, and improved the mortality rate to 24%; beta APN alone had no effect on lung mechanics or collagen content. The biochemical, functional, and structural features of bleomycin-induced lung fibrosis are amenable to control with beta APN.

Aminopropionitrile↗
PubMed1982

Relation between reduced alveolar PO2 and collagen biosynthesis in the perfused rat lung.

Collagen biosynthesis was studied in a perfused rat lung system by measuring the extent of [14C]proline incorporation into TCA-insoluble [14C]hydroxyproline-containing protein over a 2 hr perfusion period. It was found that [14C]hydroxyproline formation was linear over the 2 hr period after an initial lag period of 20 to 30 min. [14C]Hydroxyproline constituted between 5% and 6% of the total [14C]proline incorporation, indicating that about 10% of the proline incorporated went into collagen. In the presence of phosphate buffers, collagen biosynthesis was markedly reduced, although total proline incorporation was unaffected. When lungs were ventilated at progressively lower Po2's, no significant effects were observed until the Po2's were below 12 mm Hg, at which point both [14C]hydroxyproline formation and the percentage of [14C]hydroxyproline declined. The PO2 at which hydroxylation was decreased by 50% was approximately 5 mm Hg. When lungs were ventilated with a 90% carbon monoxide, 5% oxygen, 5% carbon dioxide mixture (PO2, 36 mm Hg), protein synthesis was inhibited but the proline hydroxylation system was unaffected. (J Lab Clin Med 99:441, 1982.)

Animals↗
PubMed1981

Transport of glucose analogues in rat lung.

Uptake of nonmetabolizable glucose analogues was investigated in isolated rat lungs ventilated with 5% CO2 in air and perfused with Krebs-Ringer bicarbonate medium. In some experiments, [5-3H]glucose, methyl(alpha-D-[U-14C]gluco)pyranoside (alpha-MG), 3-O-methyl-D-[U-14C]glucose (3-O-MG), or various inhibitors were added to the initial perfusate to determine glucose utilization by the rate of 3H2O production or to characterize the uptake of glucose analogues. [1,2-3H]polyethylene glycol (PEG) was used as an indicator of the extracellular water space and gave a mean value of 0.35 ml/g tissue; calculated mean intracellular H2O space was 0.48 ml/g tissue. Glucose utilization was 56.4 +/- 6.6 (mean +/- SE, n = 6) mumol . g dry wt-1 . h-1 and decreased by 61% with 3 mM phlorizin. After 1-2 h perfusion, intracellular alpha-MG concentration was 1.4-1.9 times the extracellular concentration. The mean tissue-to-medium ratio (T/M) for alpha-MG decreased by more than 30% in the presence of glucose (5.0 mM), phlorizin (0.5 mM), ouabain (0.5 mM), or the absence of external Na+. Intracellular 3-O-MG concentration did not exceed extracellular concentration during 2 h of perfusion and the mean T/M did not change with any of the inhibitors studied. The results indicate that the nonmetabolizable glucose analogue alpha-MG is accumulated against a concentration gradient by an active Na+-dependent transport process, whereas 3-O-MG is apparently taken up by a different mechanism.

3-O-Methylglucose↗
PubMed1981

Prevention of bleomycin-induced pulmonary fibrosis in the hamster by cis-4-hydroxy-l-proline.

We investigated the effect of the proline analogue cis-hydroxyproline on pulmonary fibrosis produced by intratracheal administration of bleomycin in hamsters. Two groups of animals received a single dose of bleomycin; one of these groups was also injected with cis-hydroxyproline twice daily for 30 days. Control animals received intratracheal saline. Lungs were examined on day 30. In the bleomycin group, the collagen content of lungs was 131% of the control value (p less than 0.05). Administration of cis-hydroxyproline decreased collagen accumulation to 114% of the control value (p less than 0.05). Pressure-volume curves were significantly shifted downward and to the right of control in the bleomycin group; this shift was partially prevented by cis-hydroxyproline. Morphometric studies showed that alveolar walls comprised 15% of the lung parenchyma in the control group and 19% in the bleomycin group (p less than 0.05). Administration of cis-hydroxyproline significantly decreased alveolar walls to 16% of the lung parenchyma (p less than 0.05). We conclude that cis-hydroxyproline partially prevents the chemical, structural, and functional changes of bleomycin-induced pulmonary fibrosis in the hamster.

Animals↗
PubMed1979

Effect of perfusate glucose concentration on rat lung glycolysis.

We investigated the relationship between perfusate concentration of glucose and its utilization and lactate production derived from exogenous glucose and from metabolism of endogenous substrates. Isolated rat lungs were ventilated with 5% CO2 in air and perfused for 100 min with Krebs-Ringer bicarbonate buffer containing 3% bovine serum albumin, 10(-2) U/ml insulin, [U-14C]glucose and [5-3H]glucose. Glucose utilization, total lactate production, [14C]lactate production, and 3H2O production were measured. The apparent Km and Vmax for glucose utilization were 3.4 mM and 72.5 mumol/g dry wt per h, respectively. Lactate production from endogenous substrates, calculated as the difference between total and [14C]lactate, was 37.6 +/- 2.2 mumol/g dry wt (n = 36); it was unaffected by perfusate glucose concentration and by omission of insulin, but increased threefold with anoxia. Lactate production from 1.5 mM glucose was significantly less (P less than 0.02) with insulin omitted. Glycogen content was unchanged during perfusion without glucose. These results suggest that: 1) protein catabolism contributes to lung lactate production; 2) glucose utilization by lung is not maximal at resting physiological glucose concentrations; and 3) insulin is required at low glucose concentrations for maximal glycolytic rates.

Animals↗