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G M Chisolm

Publications and source records attributed to G M Chisolm.

9 recordsLinked to original sources
PubMed1992

Vascular injury by endotoxin: changes in macromolecular transport parameters in rat aortas in vivo.

Vascular injury can lead to enhanced macromolecular transport into the arterial wall. We previously demonstrated that lipopolysaccharide (LPS) -induced injury to rat aorta in vivo caused increases in intimal and medial horseradish peroxidase (HRP) accumulation. In the present study, we quantitatively interpret these LPS-induced changes in HRP transport parameters. The parameters of interest are the permeability (PL) of the luminal blood-tissue boundary (combination of endothelium and internal elastic lamina, IEL), the effective diffusivity (D), and the convective velocity (V) across the media. The parameter values that yield the best fit of the model to the data provide a basis for understanding the tissue changes. The time of peak transmural (medial) accumulation (24 h after LPS injection) correlated with increases in PL (peak, 12-48 h) and preceded the maximum increase in V (peak, 36 h). The monotonic increase in the intimal accumulation during the 5 days after the injury has a time course distinct from the transient increases in PL and from the changes in D, which implies that endothelial permeability has only limited influence on transport beyond the intima. These data implicate the IEL as a barrier to macromolecular transport in the normal aorta and demonstrate that the endothelium and IEL work in concert to determine intimal macromolecular accumulation.

Animals↗
PubMed1992

Lipoprotein oxidation and lipoprotein-induced cell injury in diabetes.

There is ample evidence that oxidized lipoproteins exist in vivo, not only in atherosclerotic lesions, but also associated with some experimental models of diabetes. Whether the lipoprotein oxidation is an epiphenomenon of other atherogenic or diabetogenic agents or processes or whether it is causally related to lesion formation in atherosclerosis or other forms of tissue damage in people with diabetes is unresolved. Intense interest in testing these ideas derives from in vitro observations of the ways in which oxidized lipoproteins interact with cells that are unlike the interactions with native lipoproteins. Many of these altered interactions suggest known features of atherosclerotic lesions, and recent data show that antioxidant treatment reduces the progression of vascular lesions. There are reasons to believe that hyperglycemia may worsen lipid and lipoprotein oxidation. If this observation is the case in vivo, and if it is ultimately proved that lipoprotein oxidation facilitates lesion development, these events may help explain the accelerated atherosclerosis suffered by diabetic patients. The multiple pathways for which there is evidence that hyperglycemia may contribute to oxidative events--for example, by enhancing free radical production in stimulated inflammatory cells or by forming glycation products that can propagate free radical events--suggest avenues for further research and may ultimately indicate points for intervention in the various manifestations of the disease.

Animals↗
PubMed1991

Optimal design of experiments to estimate LDL transport parameters in arterial wall.

To quantify transport processes in atherosclerosis, the arterial wall is often exposed to labeled lipoproteins. In vivo experiments are desirable for estimation of transport parameters, but they are technically difficult. A dynamic mass transfer model has been developed to describe experimental transmural profiles of lipoprotein accumulation as a function of luminal permeability, diffusion, convection, and degradation. To avoid extraneous experiments and to assure successful parameter estimation, an optimal design of experiments is needed. For our purposes a design was considered optimal when it maximized the sensitivity of the model output to changes in parameter values as indicated by the determinant of the Hessian matrix of the objective function. A comparison was made between two designs: dual-time designs prescribing unequal circulation times for two distinguishable injections of labeled low-density lipoprotein (LDL) and dual-species designs requiring simultaneous circulation of LDL and tyramine-cellobiose-modified LDL. Circulation time was optimized for both designs. Although both were heavily dependent on the circulation times, dual-time designs required better preliminary knowledge of parameter values. Because labeled degradation products of the modified tracer become anchored in the arterial tissue, information about the degradation process is retained in the dual-species study. For this reason, dual-species designs were generally superior to dual-time designs.

Animals↗
PubMed1991

Lipoxygenase-mediated transformation of human low density lipoprotein to an oxidized and cytotoxic complex.

We have been studying the mechanisms involved in the oxidative modification of low density lipoprotein (LDL) that lead to its transformation to a cytotoxic complex. Here we examine the direct effect-of soybean lipoxygenase (SLO), a 15-lipoxygenase, on normal human LDL. SLO oxidized LDL and rendered it cytotoxic; agents known to interfere with lipoxygenase activity inhibited this reaction. Enhancement of both the SLO-mediated LDL oxidation and the conversion of LDL to a cytotoxin was observed when either superoxide dismutase or copper (II) (3,5,-diisopropylsalicylic acid)2, both of which dismute superoxide anion, were included during the incubation of SLO with LDL. In contrast, catalase inhibited this reaction in the presence or absence of agents that dismute superoxide anion. Thus, purified lipoxygenase can mediate LDL modification and superoxide anion inhibits this reaction, Furthermore, H2O2 is essential for SLO-mediated LDL oxidation and conversion of LDL to a cytotoxin.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1979

LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture.

Human aortic medial smooth muscle cells (SMC) and umbilical vein endothelial cells (EC) in culture were exposed to various concentrations of plasma low density (LDL) and high density (HDL) lipoproteins prepared from normolipemic donors in order to assess their effects on cell growth. So that the effects of each lipoprotein could be evaluated separately and in combination, lipoproteins were added to culture medium containing lipoprotein deficient serum (LPDS, d greater than 1.25 g/ml at a protein concentration of 4.5 mg/ml of medium). The addition of LDL at cholesterol concentrations of 160 microgram/ml of culture medium, resulted in significant reductions in both the number of SMC and EC cells per dish within 3 days of exposure (P less than 0.001, SMC; P less than 0.01, EC), when compared with LPDS controls and the starting cell numbers. This cytotoxic phenomenon was dose-related, and only at LDL cholesterol concentrations equal to or below 50 microgram/ml were no marked changes observed. In contrast, HDL at all concentrations tested produced no such deleterious effects. Autoradiographic assessment of DNA synthesis confirmed these findings. After 48 h of continuous exposure to tritiated thymidine, labeling indexes reached much lower plateaus in the LDL-treated groups.

Aorta, Thoracic↗
PubMed1979

Distribution of glycosaminoglycans in consecutive layers of the rabbit aorta.

Transmural variations in various glycosaminoglycan (GAG) fractions were determined in adventitia-free thoracic aortas from rabbits. Total glycosaminoglycan concentration decreased from intima to outer media. These data are similar to total GAG concentration in bovine and human aortas as reported by others. There is a marked decrease in the concentration of the combined chondroitin sulfate-dermatan sulfate component with increasing distance from the endothelial surface. These transmural differences are linked to the possible variation of the diffusion coefficient of a diffusing solute as a function of distance, which can affect the concentration profile of the solute.

Animals↗
PubMed1977

The distribution of labeled albumin across the rabbit thoracic aorta in vivo.

125I-albumin was injected intravenously into normal conscious rabbits. The rabbits were killed after 10 minutes to 24 hours, and the descending thoracic aorta was excises immediately, opened longitudinally, rinsed, and frozen. Samples of frozen aorta were sectioned paralled to the intimal surface and washed with trichloroacetic acid (TCA) prior to counting. TCA-soluble tissue radioactivity slowly increased with time, suggesting that 125I was cleaved gradually from the labeled albumin within the aortic wall. At up to 4 hours, transmural concentration profiles of TCA-precipitable radioactivity had steep gradients near the intimal surface, moderate gradients near the medial-advential border, and were relatively falt in the middle of the media. After 24 hours, the steep intimal gradient had disappeared. Concentrations were otherwise comparable to those at 4 hours. The rate of accumulation of TCA-precipitable radioactivity was rapid initially (measurable concentrations were found throughout the media after only 10 minutes) and decreased with time. The results are consistent with entry of 125I-albumin into the media from both the luminal and adventitial sides. Approximate calculations indicate that the albumin mass transfer resistance associated with the intimal endothelium is about 1 order of magnitude greater than that associated with the media.

Animals↗