PubMed Health⌕ Search

Biomedical subjects

J H Linehan

Publications and source records attributed to J H Linehan.

At least 19 recordsLinked to original sources
PubMed1999

Structure-function relationships in the pulmonary arterial tree.

Knowledge of the relationship between structure and function of the normal pulmonary arterial tree is necessary for understanding normal pulmonary hemodynamics and the functional consequences of the vascular remodeling that accompanies pulmonary vascular diseases. In an effort to provide a means for relating the measurable vascular geometry and vessel mechanics data to the mean pressure-flow relationship and longitudinal pressure profile, we present a mathematical model of the pulmonary arterial tree. The model is based on the observation that the normal pulmonary arterial tree is a bifurcating tree in which the parent-to-daughter diameter ratios at a bifurcation and vessel distensibility are independent of vessel diameter, and although the actual arterial tree is quite heterogeneous, the diameter of each route, through which the blood flows, tapers from the arterial inlet to essentially the same terminal arteriolar diameter. In the model the average route is represented as a tapered tube through which the blood flow decreases with distance from the inlet because of the diversion of flow at the many bifurcations along the route. The taper and flow diversion are expressed in terms of morphometric parameters obtained using various methods for summarizing morphometric data. To help put the model parameter values in perspective, we applied one such method to morphometric data obtained from perfused dog lungs. Model simulations demonstrate the sensitivity of model pressure-flow relationships to variations in the morphometric parameters. Comparisons of simulations with experimental data also raise questions as to the "hemodynamically" appropriate ways to summarize morphometric data.

Algorithms↗
PubMed1999

Detection of changes in lung tissue properties with multiple-indicator dilution.

We evaluated the potential utility of a group of indicators, each of which targets a particular tissue property, as indicators in the multiple-indicator dilution method to detect and to identify abnormalities in lung tissue properties resulting from lung injury models. We measured the pulmonary venous outflow concentration vs. time curves of [14C]diazepam, 3HOH, [14C]phenylethylamine, and a vascular reference indicator following their bolus injection into the pulmonary artery of isolated perfused rabbit lungs under different experimental conditions, resulting in changes in the lung tissue composition. The conditions included granulomatous inflammation, induced by the intravenous injection of complete Freund's adjuvant (CFA), and intratracheal fluid instillation, each of which resulted in similar increases in lung wet weight. Each of these conditions resulted in a unique pattern among the concentration vs. time outflow curves of the indicators studied. The patterns were quantified by using mathematical models describing the pulmonary disposition of each of the indicators studied. A unique model parameter vector was obtained for each condition, demonstrating the ability to detect and to identify changes in lung tissue properties by using the appropriate group of indicators in the multiple-indicator dilution method. One change that was particularly interesting was a CFA-induced change in the disposition of diazepam, suggestive of a substantial increase in peripheral-type benzodiazepine receptors in the inflamed lungs.

Animals↗
PubMed1998

Feldkamp and circle-and-line cone-beam reconstruction for 3D micro-CT of vascular networks.

Detailed morphometric knowledge of the microvascular network is needed for studies relating structure to haemodynamic function in organs like the lung. Clinical volumetric CT is limited to millimetre-order spatial resolution. Since evidence suggests that small arterioles (50 to 300 micrometres) dominate pulmonary haemodynamics, we built a micro-CT scanner, capable of imaging excised lungs in 3D with 100 microm resolution, for basic physiology research. The scanner incorporates a micro-focal (3 microm) x-ray source, an xyz theta stage and a CCD-coupled image intensifier detector. We imaged phantoms and contrast-enhanced rat lungs, reconstructing the data with either the Feldkamp or the circle-and-line cone-beam reconstruction algorithm. We present reconstructions using 180 views over 360 degrees for the circular trajectory, augmented with views from a linear scan for the circle-and-line algorithm. Especially for platelike features perpendicular to the rotation axis and remote from the midplane, the circle-and-line algorithm produces superior reconstructions compared with Feldkamp's algorithm. We conclude that the use of nonplanar source trajectories to perform micro-CT on contrast-enhanced, excised lungs can provide data useful for morphometric analysis of vascular trees, currently down to the 130 microm level.

Algorithms↗
PubMed1998

Ascorbate-mediated transplasma membrane electron transport in pulmonary arterial endothelial cells.

Pulmonary endothelial cells are capable of reducing certain electron acceptors at the luminal plasma membrane surface. Motivation for studying this phenomenon comes in part from the expectation that it may be important both as an endothelial antioxidant defense mechanism and in redox cycling of toxic free radicals. Pulmonary arterial endothelial cells in culture reduce the oxidized forms of thiazine compounds that have been used as electron acceptor probes for studying the mechanisms of transplasma membrane electron transport. However, they reduce another commonly studied electron acceptor, ferricyanide, only very slowly by comparison. In the present study, we examined the influence of ascorbate [ascorbic acid (AA)] and dehydroascorbate [dehydroascorbic acid (DHAA)] on the ferricyanide and thiazine reductase activities of the bovine pulmonary arterial endothelial cell surface. The endothelial cells were grown on microcarrier beads so that the reduction of ferricyanide and methylene blue could be studied colorimetrically in spectrophotometer cuvettes and in flow-through cell columns. The ferricyanide reductase activity could be increased 80-fold by adding DHAA to the medium, with virtually no effect on methylene blue reduction. The DHAA effect persisted after the DHAA was removed from the medium. AA also stimulated the ferricyanide reductase activity but was less potent, and the relative potencies of AA and DHAA correlated with their relative rates of uptake by the cells. The results are consistent with the hypothesis that AA is an intracellular electron donor for an endothelial plasma membrane ferricyanide reductase and that the stimulatory effect of DHAA is the result of increasing intracellular AA. Adding sufficient DHAA to markedly increase extracellular ferricyanide reduction had little effect on the plasma membrane methylene blue reductase activity, suggesting that pulmonary arterial endothelial cells have at least two separate transplasma membrane electron transport systems.

Animals↗
PubMed1998

Anatomic distribution of pulmonary vascular compliance.

Previously, the pressure changes after arterial and venous occlusion have been used to characterize the longitudinal distribution of pulmonary vascular resistance with respect to vascular compliance using compartmental models. However, the compartments have not been defined anatomically. Using video microscopy of the subpleural microcirculation, we have measured the flow changes in approximately 40-micron arterioles and venules after venous, arterial, and double occlusion maneuvers. The quasi-steady flows through these vessels after venous occlusion permitted an estimation of the compliance in three anatomic segments: arteries > 40 microns, veins > 40 microns, and vessels < 40 microns in diameter. We found that approximately 65% of the total pulmonary vascular compliance was in vessels < 40 microns, presumably mostly capillaries. The transient portions of the pressure and flow data after venous, arterial, and double occlusion were consistent with most of the arterial compliance being upstream from most of the arterial resistance and most of the venous compliance being downstream from most of the venous resistance.

Animals↗
PubMed1998

Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.

We measured the pulmonary venous concentration vs. time curves for [3H]alfentanil, [14C]lidocaine, and [3H]codeine after the bolus injection of each of these lipophilic amine compounds (LAC) and a vascular-reference indicator (fluorescein isothiocyanate-dextran) into the pulmonary artery of isolated perfused rabbit lungs. A range of flows and perfusate albumin concentrations was studied. To evaluate the information content of the data, we developed a kinetic model describing the pulmonary disposition of these LAC that was based on indicator dilution theory, and we sought a robust approach for interpreting the estimated model parameters. We found that the distribution of the kinetic model rate constants of the lipophilic amine-tissue interactions can be described by alpha, H, and psi, where alpha is a measure of the capacity of the rapidly equilibrating interactions between the lipophilic amine and the tissue; H is a measure of the equilibrium capacity of the slowly equilibrating interactions between the lipophilic amine and the tissue; and psi is the mean sojourn time. The values of alpha, H, and psi were 0.8 +/- 0.1 (SE), 0.6 +/- 0.1, and 1.6 +/- 0.5 s; 1.9 +/- 0.1, 5.3 +/- 0.4, and 5.6 +/- 0.5 s; and 1.1 +/- 0.1, 9.8 +/- 0.4, and 4.7 +/- 0.2 s for alfentanil, lidocaine, and codeine, respectively. These values for alpha, H, and psi reveal the relative dominance of the slowly equilibrating interactions for lidocaine and codeine in comparison with alfentanil. This approach to data analysis may have utility for the potential use of LAC to reveal and to quantify changes in lung tissue composition associated with lung disease.

Alfentanil↗
PubMed1998

Transit time dispersion in the pulmonary arterial tree.

Knowledge of the contributions of arterial and venous transit time dispersion to the pulmonary vascular transit time distribution is important for understanding lung function and for interpreting various kinds of data containing information about pulmonary function. Thus, to determine the dispersion of blood transit times occurring within the pulmonary arterial and venous trees, images of a bolus of contrast medium passing through the vasculature of pump-perfused dog lung lobes were acquired by using an X-ray microfocal angiography system. Time-absorbance curves from the lobar artery and vein and from selected locations within the intrapulmonary arterial tree were measured from the images. Overall dispersion within the lung lobe was determined from the difference in the first and second moments (mean transit time and variance, respectively) of the inlet arterial and outlet venous time-absorbance curves. Moments at selected locations within the arterial tree were also calculated and compared with those of the lobar artery curve. Transit times for the arterial pathways upstream from the smallest measured arteries (200-micron diameter) were less than approximately 20% of the total lung lobe mean transit time. Transit time variance among these arterial pathways (interpathway dispersion) was less than approximately 5% of the total variance imparted on the bolus as it passed through the lung lobe. On average, the dispersion that occurred along a given pathway (intrapathway dispersion) was negligible. Similar results were obtained for the venous tree. Taken together, the results suggest that most of the variation in transit time in the intrapulmonary vasculature occurs within the pulmonary capillary bed rather than in conducting arteries or veins.

Algorithms↗
PubMed1997

Regional perfusion parameters from pulmonary microfocal angiograms.

An indicator-dilution model was developed to describe transport of vascular contrast medium through an organ during acquisition of vascular dynamic contrast images. The model provides the theoretical basis for methods of determining regional blood flow, blood volume, and mean transit time from time-absorbance curves acquired from the images of tissue regions of interest (ROI) distal from the inlet site. The robustness of these methods was evaluated using a computer-simulated vessel network, which simulated the passage of a bolus of contrast medium through arterioles, networks of capillaries, and venules. The network was used to evaluate the reliability of ROI parameter estimation methods when the underlying model assumptions are violated. The shape of the ROI inlet concentration curve and moderate amounts of random noise did not affect the ability of the method to recover accurate parameter estimates. The estimates of ROI flow and transit time were degraded in the presence of significant dispersion of the inlet concentration curve as it traveled through arteries upstream from the microvascular ROI or when the flow was redistributed within the ROI. The estimates of ROI volume were relatively robust. The method was applied to image data of the dog pulmonary vasculature obtained using microfocal X-ray angiography to show that the results obtained from the simulations are consistent with actual data.

Angiography↗
PubMed1997

Pulmonary endothelial thiazine uptake: separation of cell surface reduction from intracellular reoxidation.

The objective of this study was to further evaluate the hypothesis that the accumulation of thiazine dyes, such as methylene blue, by cultured bovine pulmonary arterial endothelial cells involves reduction on the cell surface, followed by diffusion of the lipophilic reduced form of the dye into the cells and intracellular reoxidation to the relatively membrane-impermeant hydrophilic form. The specific question addressed was whether inhibition of methylene blue uptake by cyanide and azide is via inhibition of extracellular reduction or inhibition of intracellular reoxidation. We used the cell membrane-impermeant ferricyanide ion as a secondary electron acceptor to measure the extracellular reduction of methylene blue independently from its uptake by the cells. In addition, toluidine blue O, incorporated into an acrylamide polymer so that it could not permeate the cells in either its reduced or oxidized forms, was used to examine the effects of cyanide and azide on the extracellular reduction. Microscopic observations of the effect of the inhibitors on the intracellular accumulation of methylene blue were also made. The results indicate that the reduction and intracellular sequestration are separate processes and that, in doses that inhibited intracellular reoxidation, and therefore uptake and sequestration, neither cyanide nor azide had an inhibitory effect on extracellular reduction. The intracellular distribution of the observable oxidized form of the dye was consistent with oxidation of the reduced dye within subcellular organelles. The demonstration that extracellular reduction and intracellular sequestration are separate events is consistent with the hypothesized sequence of events.

Acrylic Resins↗
PubMed1997

Flow-induced vasodilation in the ferret lung.

To examine the possibility that shear stress may be a pulmonary vasodilator stimulus, we studied the effect of changing blood flow on the diameters of small pulmonary arteries in isolated perfused ferret lung lobes. The arteries studied were in the approximately 0.3- to 1.3-mm-diameter range, and the diameters were measured by using microfocal X-ray imaging. The diameters were measured at two flow rates, 10 and 40 ml/min, with the intravascular pressure in the measured vessels the same at the two flow rates as the result of venous pressure adjustment. The response to a change in flow was studied under both normoxic and hypoxic conditions. Hypoxia was used to elevate pulmonary arterial tone to increase the likelihood of detecting a vasodilator response. Under normoxic conditions, changing flow had little effect on the arterial diameters, but under hypoxic conditions the arteries were consistently larger at the higher flow than at the lower flow, even though the distending pressure was the same at the two flow rates. The results are consistent with the hypothesis that shear stress is a pulmonary vasodilator stimulus.

Animals↗
PubMed1996

Impact of angiotensin-converting enzyme substrate conformation on fractional hydrolysis in lung.

We examined the hydrolysis kinetics of benzoyl-phenylalanyl-glycyl-proline (BPGP) in the isolated perfused lung and in vitro for evidence of preferential hydrolysis of the trans isomer by angiotensin-converting enzyme (ACE). Nuclear magnetic resonance spectroscopy showed that BPGP exists as cis and trans isomers in a ratio of 44:56. After a single pass through the perfused rabbit lung over a wide range of infused BPGP concentrations, 42% of the BPGP was not hydrolyzed. In single-pass bolus-injection studies, 41% of the injected BPGP was not hydrolyzed, and very little further hydrolysis occurred in a second passage of the bolus through the lungs. In rat lung recirculation and in vitro studies of BPGP hydrolysis by ACE, approximately 60% of the substrate was hydrolyzed rapidly compared with the remaining approximately 40%, and the peptidyl-prolyl cis-trans isomerase cyclophilin increased the rate of the slower phase of the reaction in both kinds of experiments. We conclude that the rapid hydrolysis phase represents primarily the hydrolysis rate of the trans isomer and the slower phase the cis-trans isomerization rate, suggesting that the trans isomer of BPGP is preferentially hydrolyzed by ACE in the perfused lung and in vitro.

Animals↗
PubMed1995

Reduction of thiazine dyes by bovine pulmonary arterial endothelial cells in culture.

The uptake of methylene blue (MB), and toluidine blue O (TBO) by bovine pulmonary arterial endothelial cells grown on microcarrier beads was detected as a decrease in the concentration of dye in the medium after these thiazine dyes were added to the medium surrounding the cells. Because the reduced forms of these dyes are much more lipophilic than the oxidized forms, we considered the possibility that reduction of the dyes at the cell surface might have preceded the uptake by the cells. Therefore, we studied the ability of the cells to reduce a toluidine blue O-polyacrylamide polymer (TBOP), which was too large to enter the cells in either the oxidized or reduced form. The TBO moieties of the polymer were reduced by the cells, indicating that the dyes did not have to enter the cells to be reduced and that reduction can occur at, or near, the cell surface. The rate of TBOP reduction was about the same as the rate of uptake of the monomeric dyes, indicating that the cell surface reduction mechanism had a sufficient capacity to account for the monomer uptake by the cells. We also found that ferricyanide ion, which also did not permeate the cells, was reduced by the cells and that external ferricyanide inhibited the monomeric MB uptake. Thus the results with ferricyanide were also consistent with the concept that the monomeric thiazine dyes are reduced at the cell surface before the more lipophilic reduced forms are taken up by the endothelial cells.

Acrylic Resins↗
PubMed1995

Estimation of the pulmonary capillary transport function in isolated rabbit lungs.

Recently, we presented a method for estimating the pulmonary capillary volume and transport function based on the use of a reference indicator and two or more indicators that rapidly equilibrate (radially) with the tissue (i.e., the concentrations in the vascular and extravascular spaces at a given axial location are in equilibrium) during transit through the capillaries in a bolus-injection indicator dilution method (S. H. Audi, G. S. Krenz, J. H. Linehan, D. A. Rickaby, and C. A. Dawson. J. Appl. Physiol. 77:332-351, 1994). The objectives of the present study were 1) to determine whether [14C]diazepam and [3H]alfentanil equilibrate sufficiently rapidly between the vascular space and tissue and with sufficiently different pulmonary extra-vascular mean residence times to be used in a single bolus to estimate the pulmonary capillary volume and transport function using this method and 2) to estimate the pulmonary capillary volume and transit time distribution in isolated perfused rabbit lungs. Both [14C]diazepam and [3H]alfentanil were found to be rapidly equilibrating indicators by the criteria that, over a wide range of flow rates, their respective venous effluent concentration curves were nearly congruent on a time scale normalized to the lung mean transit time for the reference indicator (fluorescein isothiocyanate dextran). In addition, at a given plasma albumin concentration, [14C]diazepam had a significantly longer extravascular mean residence time than [3H]alfentanil, e.g., at 6% plasma albumin concentration, the extravascular mean residence time of [14C]diazepam was more than twice that of [3H]alfentanil. On average, the estimated pulmonary capillary volume for a 2.7-kg was approximately 4.2 ml or approximately 44% of the total pulmonary vascular volume (9.5 ml). The relative dispersion of the pulmonary capillary transport function of the rabbit was approximately 90%.

Alfentanil↗
PubMed1995

Subpleural pulmonary microvascular pressures in the dog lung.

The reported values for the pressure difference between lobar artery and subpleural arteriole and between subpleural venule and lobar vein as a fraction of the total arterial-to-venous pressure drop across the dog lung have varied considerably. We carried out the present study to provide an additional set of measurements and to determine whether it is likely that differences in venous pressure or transpulmonary pressure between studies might make a substantial contribution to variations between studies. We measured the lobar arterial pressure (Pa) to subpleural arteriole (22-60 microns diam) pressure (Pma) to subpleural venule (30-80 microns diam) pressure (Pmv) to lobar venous pressure (Pv) distribution over a range of alveolar pressures (PA; 2.5-13.1 mmHg) and venous pressures (0-24.2 mmHg) in isolated dog lung lobes using the micropuncture servo-null technique. On average, near functional residual capacity (PA = 3 mmHg) and venous pressure equal to PA, (Pa-Pma)/(Pma-Pmv)/(Pmv-Pv) was 37:30:33%. Under zone 3 conditions, there was a small positive correlation between the fractional Pa-to-Pma pressure difference and PA and Pv, but dependence of the Pmv-to-Pv fraction on PA and Pv was not consistent. The overall effects of PA and Pv on the fractional pressure drops were not sufficient to account for differences between previous studies. Under zone 2 conditions as the venous pressure was varied, the changes in Pmv were nearly equal to the changes in Pv, whereas Pma was relatively insensitive to Pv. Thus, the zone 2 results were consistent with a capillary location for the flow-limiting segment under zone 2 conditions.

Animals↗
PubMed1994

Influence of hypoxia and serotonin on small pulmonary vessels.

X-ray angiograms obtained from isolated perfused dog lungs were used to measure changes in the internal diameter of small intraparenchymal pulmonary arteries (150-1,600 microns) and veins (200-1,000 microns) in response to hypoxia or intra-arterial serotonin [5-hydroxytryptamine (5-HT)] infusion. The diameter changes in response to the two stimuli were measured over a range of stimulus-induced increases (delta Pa) in the total arteriovenous pressure drop. When the resulting delta Pa was small, all arteries in the diameter range studied constricted in response to either stimuli. The maximum decrease in diameter was approximately 25% with hypoxia and 36% with 5-HT. However, when delta Pa was large, arteries with a control diameter larger than approximately 800 microns distended with hypoxia. On the other hand, 5-HT constricted all the arteries in the size range studied regardless of the resulting magnitude of delta Pa. Hypoxia caused a small (approximately 9%) constriction in all veins in the diameter range studied independent of diameter or the magnitude of delta Pa, whereas in the concentration range studied 5-HT had no significant influence on these veins. An analysis of the potential impact of these vessels on total pulmonary vascular resistance suggested that although vessels in the size range studied contributed significantly to the total response to these two stimuli, vessels smaller than those studied also made a major contribution to the total response.

Angiography↗
PubMed1994

Airway reopening pressure in isolated rat lungs.

In a previous modeling study, we predicted that the yield pressure for airway reopening (Pyield) should depend on airway fluid surface tension (gamma) and airway radius (R), according to the relationship Pyield = 8.3 gamma/R. To test this prediction, we studied tantalum bronchograms of isolated perfused rat lungs from three rats by using microfocal X-ray imaging. Thirty-two airways with diameters ranging from 300 to 2,400 microns were recorded as the airways were collapsed and reinflated. Airway pressure was reduced transiently to -40 cmH2O to produce airway closure. Airway pressure was then slowly increased from 0 to 25 cmH2O. In each airway, the observed diameter remained constant until a Pyield was reached; at this pressure, airways were seen to "pop" open, allowing clear identification of airway reopening pressure. When Pyield was plotted against diameter at maximum inflation, the experimental data were in approximate agreement with predictions of Pyield made assuming a gamma of 35 dyn/cm. The close correspondence of the measured values with these predictions suggests that surfactant is present in these airways and facilitates airway reopening.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Pulmonary capillary transport function from flow-limited indicators.

The objective of this study was to examine the use of rapidly diffusing (flow-limited) indicators for estimating the pulmonary capillary blood volume (i.e., fraction of the lung blood volume wherein the diffusible indicators equilibrate with the tissue) and the capillary transit time distribution. Supporting theory and an application to experimental data are presented. The theory leads to the following equations, which relate the mean transit time (t), the variance (sigma 2), and the third central moment (m3) of the capillary transport function, hc(t), to the moments of the venous concentration-time curves for a vascular reference indicator, CR(t), and a flow-limited diffusible indicator, CD(t), after a bolus injection of the indicators upstream from an organ: sigma 2D - sigma 2R = ([1 + (te/tc)]2-1)sigma 2c and m3D-m3R = ([1 + (te/tc)]3-1)m3c, where te = tD - tR and tc is capillary t. The moments of hc(t) can be estimated if the injected bolus includes, along with the vascular reference indicator, at least two flow-limited diffusible indicators, each with a different te. A least-squares optimization procedure can then be used to specify the moments of hc(t). This approach was applied to isolated dog lung lobes with [14C]-diazepam as the diffusible indicator. The tissue-to-perfusate partition coefficient for [14C]diazepam could be adjusted to any desired value by altering the perfusate albumin concentration. Thus, by making a number of injections, each at a different perfusate albumin concentration, data were obtained in a manner equivalent to making one injection with a number of flow-limited diffusible indicators, each with a different te. On average, the estimated capillary volume and mean transit time were approximately 48% of the total lobar volume and mean transit time, and the relative dispersion of the hc(t) was approximately 75%.

Animals↗