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Biomedical subjects

C A Dawson

Publications and source records attributed to C A Dawson.

At least 55 records · Page 3Linked to original sources
PubMed1997

Late response to whole-lung irradiation alone and with whole-body hyperthermia in dogs.

The late effects of whole-lung irradiation with and without whole-body hyperthermia were studied in beagle dogs. The reference doses ranged from 18 to 49.5 Gy given in 1.5-Gy fractions over 6 weeks. Whole-body hyperthermia was given in three 2-h treatments to a deep rectal temperature of 42.0 degrees C. Radiation was given simultaneously with hyperthermia on those days. Physiological and histopathological responses were evaluated. Physiological changes included decreases in cardiac output, systemic blood pressure, dynamic compliance and serotonin uptake. Early changes included an increase in extravascular water and total protein in the lavage. These changes were considered mild, were compensated for and occurred only in dogs receiving doses of 40.5 Gy or greater given in 1.5-Gy fractions over 6 weeks. Histopathological changes were typical of irradiated lung and included pleural fibrosis, interstitial fibrosis, fibrotic foci, and peribronchial and perivascular fibrosis. There was no enhancement of late injury to lung by hyperthermia seen in this study.

Animals↗
PubMed1996

Intrinsic tone and distensibility of in vitro and in situ cat pulmonary arteries.

This study was designed to determine the in vitro and in situ diameter vs pressure relationship of 200- to 1,200-microns diameter pulmonary arteries in the cat. Diameter vs pressure relationships of these arteries were obtained using two methods, microscopic observation of in vitro cannulated and pressurized arteries and X-ray angiography of in situ arteries. Both in vitro and in situ arteries were studied first under normal conditions and then after reducing tone with Ca(2+)-free solution (in vitro) or papaverine (in situ). In vitro arteries commonly increased their tone in response to elevated transmural pressure, and in some cases, the diameter actually decreased as pressure increased. This behavior was not observed in the in situ arteries. The major difference between in vitro and in situ arteries was that when the in vitro arteries were relaxed, the slope of the diameter vs pressure curves increased, whereas the slope was not altered significantly by relaxation of the in situ arteries. This difference is emphasized by the increased distensibility with relaxation of the in vitro arteries but the decreased distensibility with relaxation of the in situ arteries. The results of this study suggest that, at least in the cat, small pulmonary arteries possess a mechanism that is dormant in the in situ environment within the normal lung. However, the potential for pressure-induced constriction may be unmasked by changing the vessel history and/or environment. Extrapolating results obtained from in vitro pulmonary arteries to the in situ situation should therefore be done with caution. Studies directed at what factors contribute to differences in the responses of in vitro and in situ arteries might help in understanding pulmonary vascular pathophysiology.

Angiography↗
PubMed1996

Effect of hypoxia on nitric oxide production in neonatal pig lung.

Nitric oxide (NO) synthase inhibitors potentiate hypoxic vasoconstriction (HV), suggesting that NO production during hypoxia normally acts to attenuate HV. To begin to examine the effect of hypoxia on lung NO production, we studied four groups of isolated neonatal pig lungs. In three groups of lungs, the accumulation of nitrite/nitrate (NOx-) was measured in the recirculating perfusate during ventilation with a control gas mixture (Cont), a hypoxic gas mixture (Hyp), or the control gas mixture with N omega-nitro-L-arginine methyl ester (L-NAME) added to the perfusate. Both hypoxia and L-NAME significantly increased perfusion pressure [pulmonary arterial pressure (Pa)-pulmonary venous pressure (Pv)] compared with control. NOx- accumulated in the perfusate at an average rate of 9.1 +/- 2.3 (SE) nmol/min in Cont, 3.7 +/- 0.8 nmol/min (P < 0.05 vs. control) in Hyp, and 3.7 +/- 0.6 nmol/min (P < 0.05 vs. control) in L-NAME. In the fourth group of lungs, exhaled NO output was measured during ventilation with the control gas mixture, the hypoxic gas mixture, and the control gas mixture with L-NAME added to the perfusate. Pa-Pv increased significantly with both hypoxia and L-NAME in these lungs. The exhaled NO output also decreased significantly with both hypoxia and L-NAME. These results suggest that in this preparation there was continuous production of NO that was decreased by hypoxia or L-NAME. It is not clear how the potentiation of HV by NO inhibitors and inhibition of NO production by hypoxia are linked.

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↗
PubMed1996

Electrochemical nitric oxide and nitrogen dioxide analyzer for use with inhaled nitric oxide.

The use of inhaled nitric oxide (NO) in research and clinical applications requires the monitoring of NO and its autooxidation product nitrogen dioxide (NO2) in inspired gas and in the ambient environment. We describe an inexpensive electrochemical NO and NO2 analyzer that uses a critical orifice constant-flow controller and a microprocessor crossover correction for the measurement of NO and NO2 in the concentration range relevant to the use of inhaled NO. The analyzer proved to have good accuracy and precision for NO and NO2 in the range of concentrations relevant to studies of inhaled NO. In this range, the performance was similar to that of a chemiluminescence analyzer, and the response characteristics were not affected by varying the O2 concentration of the mixtures analyzed.

Administration, Inhalation↗
PubMed1995

Cyclophilin-facilitated bradykinin inactivation in the perfused rat lung.

Cis and trans isomers of X-proline (X-Pro) bonds can influence some aspects of the kinetics of peptide metabolism. We previously used the peptidyl-prolyl cis-trans isomerase, cyclophilin, to show that angiotensin converting enzyme (ACE) preferentially hydrolyzes the trans isomer of a synthetic tripeptide that contains a C-terminal proline (Dawson et al., Am J Physiol 257:H853-H865, 1989; Merker et al., J Appl Physiol 75: 1519-1524, 1993). Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) exists as both cis and trans isomers at all three X-Pro bonds, and although its inactivation in the lung by pulmonary endothelial peptidases is extensive, commonly a small fraction of the peptide survives passage through the lung. To determine whether the presence of cis X-Pro bonds might limit the extent of bradykinin metabolism in the lung, we studied inactivation of bradykinin by the isolated perfused rat lung using the rabbit jugular vein superfused with the pulmonary venous effluent as a bioassay for bradykinin. A large fraction (> 90%) of the bradykinin in a bolus injection was inactivated in a single transit through the pulmonary circulation, but a detectable fraction emerged in the venous effluent. The addition of cyclophilin to the bradykinin in the bolus reduced the bradykinin emerging from the lungs to virtually undetectable levels. When the isomerase inhibitor cyclosporin A was included with bradykinin and cyclophilin in the injectate, this effect of cyclophilin was reversed. These observations suggest that the fraction of bradykinin that normally survives passage through the lungs contains isomers that have at least one X-Pro bond that is refractory to enzymatic inactivation and whose isomerization time constant is significantly longer than the pulmonary capillary transit time.

Amino Acid Isomerases↗
PubMed1995

Lung perfusion with chemotherapy in patients with unresectable metastatic sarcoma to the lung or diffuse bronchioloalveolar carcinoma.

Eight patients with metastatic sarcoma to the lung (n = 4) or diffuse bronchioloalveolar carcinoma of the lung (n = 4) underwent isolated lung perfusion with chemotherapy in a pilot study. Ages ranged from 18 to 60 years and half were female. The left lung was perfused in three patients (single lung perfusion) and both lungs in five patients (total lung perfusion). Perfusions ranged from 45 to 60 minutes at ambient or normothermic temperatures. One patient received perfusion at moderate hyperthermia (40 degrees C). Escalating doses of doxorubicin (1 to 10 micrograms/ml perfusate) was used in six patients, whereas two received cisplatin (14 and 20 micrograms/ml perfusate). There were two major complications and no objective responses. The isolated perfusion systems gave excellent separation between systemic and pulmonary circulations with zero to 15% of the measured peak drug concentration of the pulmonary perfusate detected in the systemic circulation. Drug concentrations in normal lung and tumor generally increased with higher drug dosages and drug was detectable in mediastinal lymph nodes of three out of four patients in whom sampling was done. Isolated lung perfusion with chemotherapy can be done safely in patients with lung malignancies and evidence suggests that higher drug dosages should be well tolerated.

Adenocarcinoma, Bronchiolo-Alveolar↗
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↗
PubMed1995

Hydroxyl radical production and lung injury in the rat following silica or titanium dioxide instillation in vivo.

The hydroxyl radical (.OH) is a highly reactive oxygen free radical that has been implicated as a cause of lung injury following exposure to silica and silicates. Despite evidence that silica generates .OH in vitro, there has been no previous demonstration of in vivo production of .OH after exposure to nonfibrous mineral oxide dusts. We tested the hypothesis that instillation of silica into rat lungs is associated with greater .OH production and acute lung inflammation in vivo relative to the instillation of a less toxic nonsilicate particle, titanium dioxide. The production of .OH in the lungs following dust instillation was measured using sodium salicylate as an .OH trap. Seven days after dust exposure, the rats were given intraperitoneal salicylate, the lungs isolated, and salicylate hydroxylation products (2,3- and 2,5-dihydroxybenzoic acid), reflecting .OH, were measured. There was significantly more 2,3-dihydroxybenzoic acid in silica-exposed lungs compared with lungs instilled with titanium dioxide. In addition, the instillation of silica into rat lungs in vivo was associated with a greater acute inflammatory response. We conclude that following in vivo exposure, silica stimulates greater .OH production relative to the less toxic particle, titanium dioxide. These differences in .OH generation correspond to disparities in acute lung inflammation.

Animals↗
PubMed1994

Latex-induced dermal and pulmonary hypersensitivity in rabbits.

BACKGROUND: Natural rubber latex (NRL) causes immediate, IgE-mast cell-mediated reactions in sensitized individuals, especially among health care workers and children with spina bifida. The immunopathogenesis of the reaction is obscure. METHODS: To study the immunologic mechanisms of NRL allergy, rabbits were sensitized with two nonammoniated and one ammoniated NRL antigens. Subcutaneous and intratracheal injections were used to immunize rabbits. Intradermal skin tests, IgG antibodies against NRL in serum and lung lavage fluid, and pulmonary histologic features were evaluated. RESULTS: One of nine sensitized rabbits died of anaphylaxis immediately after the third intratracheal injection with nonammoniated NRL. All sensitized rabbits, but not the controls, showed an immediate wheal and flare reaction in intradermal skin testing with NRL antigens. A positive skin reaction was detected 6 and 48 hours after the intradermal injections in four of five sensitized rabbits. A significant increase in NRL-specific IgG antibodies was detected in serum and lung lavage fluid of immunized rabbits. Lung histologic evaluation of NRL-sensitized rabbits showed a granulomatous interstitial and bronchial inflammation with a predominance of eosinophils and histiocytes in both intratracheally and subcutaneously sensitized rabbits. Vasculitis, hypertrophia, and contraction of pulmonary arteries could be detected in sensitized animals. CONCLUSION: The results of the first NRL rabbit model study indicate that eosinophils and IgE antibodies play a major role in the immunopathogenesis of NRL-induced allergy and anaphylaxis. A wide range of inflammatory responses detected in rabbits injected by subcutaneous route without intratracheal exposure suggests that NRL exposure may pose a risk for a subsequent systemic reaction.

Anaphylaxis↗
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↗
PubMed1994

Impact of parallel heterogeneity on a continuum model of the pulmonary arterial tree.

Model arterial trees were constructed following rules consistent with morphometric data, Nj = (Dj/Da)-beta 1 and Lj = La(Dj/Da)beta 2, where Nj, Dj, and Lj are number, diameter, and length, respectively, of vessels in the jth level; Da and La are diameter and length, respectively, of the inlet artery, and -beta 1 and beta 2 are power law slopes relating vessel number and length, respectively, to vessel diameter. Simulated heterogeneous trees approximating these rules were constructed by assigning vessel diameters Dm = Da[2/(m + 1)]1/beta 1, such that m-1 vessels were larger than Dm (vessel length proportional to diameter). Vessels were connected, forming random bifurcating trees. Longitudinal intravascular pressure [P(Qcum)] with respect to cumulative vascular volume [Qcum] was computed for Poiseuille flow. Strahler-ordered tree morphometry yielded estimates of La, Da, beta 1, beta 2, and mean number ratio (B); B is defined by Nk + 1 = Bk, where k is total number of Strahler orders minus Strahler order number. The parameters were used in P(Qcum) = Pa [formula: see text] and the resulting P(Qcum) relationship was compared with that of the simulated tree, where Pa is total arterial pressure drop, Q is flow rate, Ra = (128 microLa)/(pi D4a (where mu is blood viscosity), and Qa (volume of inlet artery) = 1/4D2a pi La. Results indicate that the equation, originally developed for homogeneous trees (J. Appl. Physiol. 72: 2225-2237, 1992), provides a good approximation to the heterogeneous tree P(Qcum).

Algorithms↗
PubMed1994

Edema development and recovery in neurogenic pulmonary edema.

We determined the time course of changes in extravascular lung water (EVLW) that occur after massive sympathetic activation produced by intracisternal veratrine administration in chloralose-anesthetized dogs. Three groups of dogs were studied. In the first group (n = 9), acute increases in EVLW (occurring within minutes) were determined both by measuring extravascular thermal volume and by gravimetric analysis. In the second (n = 6) and third (n = 7) groups, changes in EVLW were followed for 2-3 h after veratrine administration. Extravascular thermal volume was measured in the second group. In the third group, right atrial injections of a vascular indicator (125I-labeled serum albumin) and an extravascular indicator (3HOH) were made while blood was sampled from the pulmonary artery (PA) and left atrium, and EVLW was determined by deconvolution of the left atrial and PA concentration-time curves. Indicator-dilution and gravimetric EVLW increased acutely only in dogs in which PA pressure exceeded 60 Torr, with two- to four-fold increases in EVLW being observed in dogs that developed the highest PA pressures (maximum 94 Torr). Thus, severe edema can develop rapidly after massive sympathetic nervous system activation but requires extreme degrees of pulmonary hypertension. In several dogs after the acute increase in EVLW associated with the pulmonary hypertension, the indicator-dilution EVLW decreased with time. These decreases appear to effect clearance of edema fluid rather than alterations in perfusion.

Animals↗