Biomedical subjects

O Mathieu-Costello

Publications and source records attributed to O Mathieu-Costello.

At least 37 records · Page 2Linked to original sources

PubMed1997

Very high pressures are required to cause stress failure of pulmonary capillaries in thoroughbred racehorses.

Thoroughbred horses develop extremely high pulmonary vascular pressures during galloping, all horses in training develop exercise-induced pulmonary hemorrhage, and we have shown that this is caused by stress failure of pulmonary capillaries. It is known that the capillary transmural pressure (Ptm) necessary for stress failure is higher in dogs than in rabbits. The present study was designed to determine this value in horses. The lungs from 15 Thoroughbred horses were perfused with autologous blood at Ptm values (midlung) of 25, 50, 75, 100 and 150 mmHg, and then perfusion fixed, and samples (dorsal and ventral, from caudal region) were examined by electron microscopy. Few disruptions of capillary endothelium were observed at Ptm < or = 75 mmHg, and 5.3 +/- 2.2 and 4.3 +/- 0.7 breaks/mm endothelium were found at 100 and 150 mmHg Ptm, respectively. Blood-gas barrier thickness did not change with Ptm. At low Ptm, interstitial thickness was greater than previously found in rabbits but not in dogs. We conclude that the Ptm required to cause stress failure of pulmonary capillaries is between 75 and 100 mmHg and is greater in Thoroughbred horses than in both rabbits and dogs.

Animals↗

PubMed1997

High lung inflation increases mRNA levels of ECM components and growth factors in lung parenchyma.

Remodeling of pulmonary capillaries occurs after chronic increases in capillary pressure (e.g., mitral stenosis). Also, remodeling of pulmonary arteries begins within 4 h of increased wall stress and is endothelium dependent. We have previously shown that high lung inflation increases wall stress in pulmonary capillaries. This study was designed to determine whether high lung inflation induces remodeling of the extracellular matrix (ECM) in lung parenchyma. Open-chest rabbits were ventilated for 4 h with 9-cmH2O positive end-expiratory pressure (PEEP) on one lung and 1-cmH2O PEEP on the other (High-PEEP group), or with 2-cmH2O PEEP on both lungs (Low-PEEP group). An additional untreated control group was also included. We found increased levels of mRNA in both lungs of High-PEEP rabbits (compared with both the Low-PEEP and untreated groups) for alpha1(III) and alpha2(IV) procollagen, fibronectin, basic fibroblast growth factor, and transforming growth factor-beta1. In contrast, alpha2(I) procollagen and vascular endothelial growth factor mRNA levels were not changed. We conclude that high lung inflation for 4 h increases mRNA levels of ECM components and growth factors in lung parenchyma.

Animals↗

PubMed1996

Fiber capillarization in flight muscle of pigeons native and flying at altitude.

We examined structural characteristics for fiber O2 supply in the highly aerobic flight muscle of 5 pigeons (Columbia livia; body mass 223--317 g) native and actively flying at altitude (La Paz, Bolivia; 3750 m). Whereas deep sites were significantly more aerobic and highly vascularized than superficial in altitude (A) but not sea-level (SL) group, both sites showed a number of similarities between the two groups. The cross-sectional area of aerobic fibers (> or = 90% of fiber number) linearly increased with body mass (r 0.84; P < 0.0005) but was not smaller in A for their body mass, and there was no reduction in the size of glycolytic fibers compared to SL. The relationships between fiber capillarization and the sectional area of aerobic fibers in transverse sections or mitochondrial volume density were not altered in A compared to SL. The results indicate that the factors which determine the relationships between fiber capillarization and ultrastructure in the muscles were not altered by the adaptation to altitude. Differences between samples were related to the relative sectional area of aerobic fibers and mitochondrial volume density, not the chronic exposure to altitude.

Altitude↗

PubMed1996

Structural basis for oxygen delivery: muscle capillaries and manifolds in tuna red muscle.

We summarize our morphometric data on fiber vascularization and aerobic capacity in red muscle of tuna (Katsuwonus pelamis), compared to intensely aerobic flight muscles of hummingbird (Selasphorus rufus, BW 3-4 g) and bat (Eptesius fuscus, BW 15-16 g, Pipistrellus hesperus, BW 3-5 g). Three characteristic features of high flux paths for oxygen: (a) small fiber size, (b) dense capillary network and (c) high mitochondrial volume density were found in tuna, but they were not as pronounced as in hummingbird and bat flight muscles. A particular arrangement of capillary manifolds, also seen in flight muscle of birds but not in bats, was found in tuna, forming dense envelopes of capillary branches around portions of muscle fibers. However, all indexes of fiber capillarization were relatively low in tuna red muscle for its mitochondrial volume, compared with other intensely aerobic muscles. Capillary length per unit volume of mitochondria, and capillary surface per mitochondrial inner (and outer) membrane surface area, were about one half of those in hummingbird or bat flight muscles. Consistent differences exist in the size of the capillary network for the size of the mitochondrial compartment in highly aerobic red muscle of tuna compared with bird and mammal.

Aerobiosis↗

PubMed1996

Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart.

Increased coronary blood vessel development could potentially benefit patients with ischemic heart disease. In a model of stress-induced myocardial ischemia, intracoronary injection of a recombinant adenovirus expressing human fibroblast growth factor-5 (FGF-5) resulted in messenger RNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved, effects that persisted for 12 weeks. Improved blood flow and function were associated with evidence of angiogenesis. This report documents, for the first time, successful amelioration of abnormalities in myocardial blood flow and function following in vivo gene transfer.

Adenoviruses, Human↗

PubMed1996

In vitro activity of the antimicrobial peptides human and rabbit defensins and porcine leukocyte protegrin against Mycobacterium tuberculosis.

Three independent assay methods were used to investigate the activities of antimicrobial peptides (human and rabbit defensins and protegrin from porcine leukocytes) against Mycobacterium tuberculosis in vitro. M. tuberculosis H37Ra was cultured in the presence of human neutrophil peptide 1, synthetic rabbit neutrophil peptide 1, or porcine protegrin 1 at 37 degrees C for 6 to 48 h, and antimycobacterial activity was measured by CFU assay. These peptides at a concentration of 50 microg/ml showed significant antibacterial effects on M. tuberculosis after 24 and 48 h of incubation (85.9 to 97.5% at 24 h and 91.6 to 99.4% at 48 h). A radiometric method and a radial diffusion assay confirmed these observations. Antibacterial activity against M. tuberculosis was independent of calcium (1.0 mM) or magnesium (1.0 mM) and not inhibited by sodium chloride (100 mM). The optimal pH for antibacterial activity against M. tuberculosis was greater than 4.0. Three clinical isolates of M. tuberculosis were also studied, and these peptides showed 86.3 to 99.0% reduction in CFU of these organisms. Morphological studies using scanning electron microscopy showed that defensins caused lesions on the surface of H37Ra. These observations suggest that antimicrobial peptides such as defensins and protegrins may represent an important component of the host defense mechanism against M. tuberculosis and offer a potential new approach to therapy.

Animals↗

PubMed1996

Capillary-to-fiber surface ratio in rat fast-twitch hindlimb muscles after chronic electrical stimulation.

We examined the relative plasticity of capillaries and fiber mitochondria in rat fast-twitch hindlimb muscles in response to chronic electrical stimulation. Specifically we addressed whether the size of the capillary-fiber interface increases in proportion to fiber mitochondrial volume, inasmuch as fiber aerobic capacity increases severalfold with chronic stimulation. Tibialis anterior and extensor digitorum longus muscles of six rats [367 +/- 17 (SD) g body wt] were stimulated (10 Hz, 8 h/day, 7 days/wk) for 28 consecutive days. Subsequently they were perfusion fixed in situ and stimulated, and contralateral control samples from the midbelly were processed for electron microscopy and morphometry. Capillary length density, capillary-to-fiber ratio, and fiber mitochondrial volume density increased two- to threefold in stimulated muscles, with no change in fiber or capillary diameter. Capillary-to-fiber surface area ratio per fiber unit mitochondrial volume was unchanged in stimulated muscles compared with contralateral controls, indicating a proportional increase in the size of the capillary-fiber interface and fiber mitochondrial volume in the muscles after chronic electrical stimulation.

Animals↗

PubMed1996

Relationship between fiber capillarization and mitochondrial volume density in control and trained rat soleus and plantaris muscles.

OBJECTIVE: The majority of investigations have demonstrated a strong relationship between muscle capillarity and oxidative capacity. There is, however, evidence that the capacities for O2 supply and utilization can be dissociated. Also, metabolite removal rather than O2 supply may represent the predominant design constraint placed on the capillary bed in some muscles (i.e, fast-twitch glycolytic). Recent evidence suggests that the principal barrier to O2 diffusion in skeletal muscle resides between the red blood cell and the immediately subjacent sarcolemmal space. Consequently, if the primary design constraint placed on the capillary bed is to facilitate O2 exchange, we hypothesized that capillary surface per fiber surface should be correlated with the mitochondrial volume subserved. Thus, the purpose of this study was to investigate whether one single relationship would be found between the capillary-to-fiber surface ratio and fiber mitochondrial volume in slow- (soleus) and fast-twitch (plantaris) muscle and whether this relationship would be preserved after training. METHODS: Rats were exercise-trained on a motor-driven treadmill up to 60 min/day, 5 days/week for 4 weeks at an intensity calculated to elicit congruent to 75% VO2max. Following training, soleus (S) and plantaris (P) muscles were removed under deep anesthesia for citrate synthase analysis, and the contralateral limb was perfusion-fixed in situ with glutaraldehyde and analyzed morphometrically under light and electron microscopy. RESULTS: Training significantly (p < 0.05) increased citrate synthase activity and capillary-to-fiber ratio both in S and P muscles. For all muscles combined (i.e., S and P, control and trained), the capillary-to-fiber surface ratio significantly correlated with mitochondrial volume per unit fiber length (r = 0.64). CONCLUSIONS: Our finding of a single relationship between the capillary-to-fiber surface ratio and fiber mitochondrial volume across the muscles is consistent with the notion that the size of the capillary bed in muscles comprised principally of either slow-twitch oxidative or mixed fast-twitch oxidative glycolytic and fast-twitch glycolytic fibers is primarily designed to meet fiber requirements for O2 exchange, and that an important site for O2 diffusion resistance is at the capillary-fiber interface. In addition, capillary-to-fiber surface and fiber mitochondrial volume increased in similar proportions, i.e., the relationship between the two variables was preserved after endurance training.

Animals↗

PubMed1995

Vulnerability of pulmonary capillaries in heart disease.

The pulmonary blood-gas barrier presents a dilemma. It must be extremely thin for efficient gas exchange. However, it also needs to be immensely strong because the stresses in the pulmonary capillary wall become extremely high when the capillary pressure rises. Stress failure of the capillaries occurs in several pathological conditions. It causes high-permeability edema as in neurogenic pulmonary edema or high-altitude pulmonary edema; alveolar hemorrhage, which occurs in all galloping racehorses; or a combination of the two as in severe congestive heart failure. The vulnerability of the capillary wall to increased mechanical stress has not previously been sufficiently appreciated.

Animals↗

PubMed1995

Microvascular response to ischemia, and endothelial ultrastructure, in disused skeletal muscle.

It has previously been demonstrated that muscle atrophy associated with aging and disuse is accompanied by changes in microvascular function including absolute loss of capillaries, increased mean red blood cell velocity (VRBC), and absence of reactive hyperemia. The purpose of the present study was to determine whether disuse could account for these changes. The right extensor digitorum longus muscle in male Fisher 344 rats was subjected to 15 days of disuse through the neural application of tetrodotoxin (TTX). Microvascular function, as assessed using intravital microscopy, was compared for muscles from control (n = 8) and TTX-treated (n = 5) animals. The TTX-induced disuse was associated with a 40.5% decrease in muscle weight, a 51.6% decrease in fiber cross-sectional area, a 62% decrease in mitochondrial volume density, and increased capillary damage (TTX, 11% control, 1.1%). Although capillary density in the disused muscle increased (by 139%), when corrected for muscle atrophy, the absolute number of capillaries was maintained. With TTX disuse, VRBC heterogeneity was not different from that in the control rats while the mean velocity increased 3.18x. TTX disuse did not alter the pattern of reactive hyperemia following 30 min of complete ischemia. These results suggest that short-term TTX-induced atrophy affects both microvascular structure and resting state blood flow in rat skeletal muscle, but it does not affect the vascular responsiveness following a metabolic challenge.

Animals↗

PubMed1995

Effect of increased duration of high perfusion pressure on stress failure of pulmonary capillaries.

We have previously shown that raising the capillary transmural pressure (Ptm) in rabbit lung causes disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers of the wall. In those studies the lungs were perfused with autologous blood (1 min), then saline/dextran (3 min), followed by glutaraldehyde fixative (10 min), all at the same pressure. The present study was designed to determine whether increasing the time of exposure of the capillaries to the increased pressure altered the frequency of stress failure. The procedure was identical to that of the previous study except that the duration of the blood perfusion was extended from 1 to 10 and 100 min. We chose a Ptm of 32.5 cm H2O because our previous studies showed that this caused only a few disruptions per millimeter endothelial and epithelial boundary length (0.7 +/- 0.4 and 0.9 +/- 0.6 (SE), respectively). Ten New Zealand white rabbit lungs were perfused with autologous blood plus homologous blood from additional rabbits for 10 and 100 min. After 100 min of blood perfusion the number of disruptions per millimeter endothelial and epithelial boundary length (0.66 +/- 0.4 and 0.52 +/- 0.33 (SE), respectively) was not significantly different from the earlier study. Thus, increasing the duration of the increased Ptm during blood perfusion by 100-fold did not alter the incidence of stress failure. These results indicated that any viscoelastic behavior resulting in further strain and ultimately failure of the capillary walls is insignificant over a wide range of exposure times to increased pressure under the conditions of this study.

Animals↗

PubMed1995

Transmural distribution of capillary morphology as a function of coronary perfusion pressure in the resting canine heart.

Changes in coronary perfusion pressure lead to alterations in intracoronary myocardial volume that may be associated with regionally altered microvascular morphology. Transmural variations in coronary capillary geometry were quantified as a function of coronary perfusion pressure in glutaraldehyde-fixed canine hearts. Capillary volume fractions, diameter, numerical density, anisotropy, and sarcomere length were measured using computer analysis of light microscopic images of sections taken transverse or longitudinal to the muscle fiber axis. Capillary volume was 4-6% of myocardial wall volume and exhibited a significant transmural gradient, increasing from epicardium to endocardium. Vessels 4 to 5 microns in diameter with a density of 2900 mm-2 appear to increase in diameter and alter their cross-sectional shape with increasing pressure, rather than increasing in number, suggesting an effective distensibility of approximately 0.007 mm Hg-1. Quantification of vessel anisotropy was directly related to cross-sectional shape and demonstrated that the capillaries are highly oriented. These findings indicate that intramyocardial capacitance is at least in part associated with nonhomogeneous changes in coronary capillary morphology with altered perfusion pressure.

Animals↗

PubMed1995

Stress failure of pulmonary capillaries as a limiting factor for maximal exercise.

The pulmonary blood-gas barrier has a basic physiological dilemma. On the one hand it needs to be extremely thin for efficient gas exchange. On the other hand it also needs to be immensely strong because the stresses on the pulmonary capillary wall become extremely high when the capillary pressure rises on exercise. Maximal hydrostatic pressures in human pulmonary capillaries during exercise are not accurately known but must exceed 30 mmHg. In some animals, for example thoroughbred horses, the capillary pressure rises to about 100 mmHg. These pressures cause stresses in the capillary wall of 5-10 x 10(4) N.m-2 (50-100 kPa) which approach the breaking strength of collagen. The strength of the capillary wall on the thin side of the blood-gas barrier can be attributed to the type IV collagen of the extracellular matrix. Raising the capillary pressure to similar levels in experimental preparations causes ultrastructural changes in the wall including disruption of the capillary endothelium, alveolar epithelium, and basement membrane in the interstitium. Essentially all thoroughbred racehorses bleed into their lungs during exercise because they break their capillaries, and some elite human athletes apparently do the same. Avoiding stress failure of pulmonary capillaries poses a challenging problem for some species. Stress failure is a hitherto overlooked factor limiting maximal exercise.

Animals↗

PubMed1995

Pulmonary capillaries are more resistant to stress failure in dogs than in rabbits.

We previously showed that stress failure of pulmonary capillaries occurs at transmural pressures of approximately 50 cmH2O (40 mmHg) and above in rabbit lung. In this study, we examined whether pulmonary capillaries are more resistant to failure in dogs than in rabbits. This might be expected because of the greater athletic ability of dogs and therefore their presumably greater tolerance to large cardiac outputs and higher pulmonary vascular pressures. The lungs of 12 anesthetized mongrel dogs [22.1 +/- 5.2 (SD) kg] were perfused in situ with autologous blood and then with saline-dextran (5 min) and glutaraldehyde solution (10 min), all three perfusions at the same preset transmural pressure of 32.5, 72.5, 92.5, or 112.5 cmH2O. In dogs, the stress failure curves relating break number per millimeter of epithelium and endothelium were right shifted by approximately 40 cmH2O compared with rabbits. Blood-gas barrier thickness was significantly greater than in rabbits at 32.5 cmH2O, and unlike in rabbits, neither total nor interstitial thickness increased significantly with increasing pressure. These results indicate that pulmonary capillaries are more resistant to stress failure in dogs than rabbits.

Animals↗

PubMed1995

Effect of reducing alveolar surface tension on stress failure in pulmonary capillaries.

We previously showed that when pulmonary capillaries are exposed to high transmural pressures, stress failure of the blood-gas barrier occurs. It has been suggested that the surface tension of the alveolar lining layer may protect against stress failure because at high transmural pressures the capillaries bulge into the alveolar spaces. To test this hypothesis, we abolished the gas-liquid surface tension of the alveoli by filling rabbit lungs with normal saline. The lungs were then perfused at capillary transmural pressures of 32.5 or 52.5 cmH2O for 1 min with autologous blood, the blood was washed out with a saline-dextran mixture (3 min), and the lungs were fixed for electron microscopy with buffered glutaraldehyde; all perfusions were done at the same pressure. The frequency of breaks was measured in the capillary endothelial layer, alveolar epithelial layer, and basement membranes, and the data were compared with those in air-filled lungs at the same capillary transmural pressure and lung volume. We found that the frequency of breaks in the endothelium was not significantly different between air and saline filling and that there were fewer breaks in the outer boundary of the epithelial cells. By contrast, after saline filling, a larger number of breaks were seen in the inner boundary of the epithelium. The frequency of disruptions of the inner boundary of the epithelium was closely correlated with the volume of edema fluid collected at the trachea during the perfusion. These breaks in the inner boundary of the epithelium had not previously been seen in air-filled lungs exposed to the same pressures. The results suggest that abolishing the surface tension of the alveolar lining layer removes support from parts of the blood-gas barrier when the capillaries are subjected to a high transmural pressure but that not all portions of the barrier are subjected to the same forces.

Animals↗

PubMed1995

Pulmonary microvascular permeability. Responses to high vascular pressure after induction of pacing-induced heart failure in dogs.

The pressure threshold for injury of pulmonary capillaries is approximately 50 to 55 cm H2O in the canine lung, as measured by changes in the filtration coefficient (Kf,c). Since the pulmonary endothelial basement membrane has been observed to thicken in patients with heart failure and pulmonary venous hypertension, we hypothesized that both baseline permeability and the threshold for high-vascular-pressure injury would be altered as a result. Dogs (n = 12) were chronically paced at 245 beats per minute for approximately 4 weeks, then were paced at 225 beats per minute for an additional 3 weeks. Lung lobes from anesthetized paced dogs and additional control dogs (n = 14) were then isolated, ventilated, and perfused with blood. Although vascular resistance was increased nearly threefold and vascular compliance reduced by 50% in the paced group, Kf,c referenced to 1 g blood-free dry weight was no different from control. Despite this lack of difference at normal pulmonary vascular pressures, several significant results were obtained. First, in the paced group there was a significant increase in the threshold for high-vascular-pressure injury: Kf,c measured at pulmonary vascular pressures commonly seen in heart failure (20 to 50 cm H2O) were significantly less in this group compared with control. Model predictions showed that in vivo, this difference in Kf,c would result in a 50% reduction in the amount of water and protein cleared across the pulmonary capillary endothelial barrier in the paced group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Pathogenesis of high-altitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries.

The pathogenesis of high-altitude pulmonary oedema (HAPE) is disputed. Recent reports show a strong correlation between the occurrence of HAPE and pulmonary artery pressure, and it is known that the oedema is of the high-permeability type. We have, therefore, proposed that HAPE is caused by ultrastructural damage to pulmonary capillaries as a result of stress failure of their walls. However, no satisfactory electron microscopy studies are available in patients with HAPE, and animal models are difficult to find. Madison strain Sprague-Dawley rats show a brisk pulmonary pressure response to acute hypoxia and are susceptible to HAPE. We exposed 13 Madison rats to a pressure of 294 torr for up to 12.5 h, or 4 rats to 236 torr for up to 8 h. Pulmonary arterial or right ventricular systolic pressures measured with a catheter increased from 30.5 +/- 0.5 (SEM) in controls (n = 4) to 48 +/- 2 torr (n = 11). The lungs were fixed for electron microscopy with intravascular glutaraldehyde. Frothy bloodstained fluid was seen in the trachea of three animals. Ultrastructural examination showed evidence of stress failure of pulmonary capillaries, including disruption of the capillary endothelial layer, or all layers of the wall, swelling of the alveolar epithelial layer, red blood cells (RBCs) and oedematous fluid in the alveolar wall interstitium, proteinaceous fluid and RBCs in the alveolar spaces, and fluid-filled protrusions of the endothelium into the capillary lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Altitude Sickness↗

PubMed1994

Morphometry of the size of the capillary-to-fiber interface in muscles.

Capillary-to-fiber perimeter ratio is a morphometric estimate of muscle capillarity in transverse sections which accounts for the three-dimensional arrangement of the capillary network. We compared different methods for estimating capillary-to-fiber perimeter ratio in muscles with large differences in fiber size and capillary density or geometry (hummingbird and bat flight muscle, bat hindlimb, tuna red muscle and rat M. soleus). There was no significant difference between light and electron microscopy estimates of capillary-to-fiber perimeter ratio by direct intersection-counting in transverse sections. Calculated values via capillary surface per fiber volume and fiber cross-sectional area/perimeter were not significantly different from those obtained by direct intersection-counting in muscle transverse sections in any muscle. A closer estimate of capillary-to-fiber perimeter ratio to that obtained by direct intersection-counting in transverse sections was calculated via capillary surface density than capillary length per fiber volume and capillary diameter, possibly because of the greater number of variables used to calculate capillary-to-fiber perimeter ratio via capillary length density and diameter. A greater capillary-to-fiber perimeter ratio was found in hummingbird and bat flight muscle than in the other muscles, consistent with an important role of the capillary-to-fiber interface in determining O2 flux rates and measurements of mitochondrial respiratory rates in flying hummingbird that are about two times greater than those in locomotry muscles of mammals running at VO2max.

Animals↗