Perspectives in endothelial cell biology.
Explore the source record for details and available documents.
Cell Adhesion↗
Biomedical subjects
A P Fishman
Publications and source records attributed to A P Fishman.
Primary pulmonary hypertension. A national prospective study.
A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (+/- SD) of 36 +/- 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLCO), and hypoxemia with hypocapnia. The mean (+/- SD) right atrial pressure was 9.7 +/- 6 mm Hg; mean pulmonary artery pressure, 60 +/- 18 mm Hg; cardiac index, 2.3 +/- 0.9 L/min X m2; and pulmonary vascular resistance index, 26 +/- 14 mm Hg/L/min X m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.
Adolescent↗
Effect of 100% O2 on passage of uncharged dextrans from blood to lung lymph.
Since charge as well as size may influence the passage of plasma proteins from blood to lung lymph, we used uncharged dextrans as tracers to study the effects of hyperoxic lung injury on the molecular sieving properties of the pulmonary microcirculation in unanesthetized sheep. Polydisperse [3H]dextran was infused intravenously into five sheep before and after the animals breathed 100% O2 until lymph flow increased threefold (66-84 h). Lymph-to-plasma concentration ratios (L/P) were determined for [3H]dextran fractions of graded molecular sizes (1.6-8.4 nm effective radius) from samples obtained during the infusions. Before hyperoxia the blood-lymph barrier was highly restrictive to transport of [3H]dextrans above 5.0 nm in radius; steady-state L/P for these molecules averaged 0.03 or less. After the sheep breathed 100% O2, [3H]dextrans as large as 8.4 nm radius appeared in the lymph. Posthyperoxia, the L/P were significantly increased relative to prehyperoxia base-line values for every [3H]dextran fraction larger than 2.0 nm radius (P less than 0.05). In contrast, neither the L/P for albumin or total protein changed significantly. At autopsy, electron microscopy showed widespread damage to the endothelium of the alveolar capillaries with infrequent gaps between endothelial cells. In two control sheep, inhalation of compressed air for 96 h had no effect on lymph flow or L/P for the [3H]dextrans. We conclude that O2 poisoning reduced the selective sieving of uncharged dextrans across the blood-lymph barrier of the lungs and allowed larger dextrans to enter the lymph. These larger molecules may have leaked from the pulmonary microcirculation via disruptions in the continuity of the endothelial lining.
Animals↗
Effects of increased ventilation on lung lymph flow in unanesthetized sheep.
To determine the effect of an increase in spontaneous minute ventilation on lung fluid balance, we added external dead space to the breathing circuit of six tracheostomized, unanesthetized, spontaneously breathing sheep in which lung lymph fistulas had been created surgically. The addition of 120-180 ml of dead space caused minute ventilation to increase by 50-100% (secondary to increases in both tidal volume and frequency), without changing pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, or arterial blood gas tensions. The increase in spontaneous ventilation was associated with an average increase of 27% in lung lymph flow (P less than 0.05) and an average reduction of 11% in the lymph-to-plasma concentration ratio (L/P) for total protein (P less than 0.05). Lymph flow and L/P for total protein approached stable values after 2-3 h of hyperpnea, and the increase in lymph flow persisted for at least 18 h of dead-space breathing. Removal of dead space was associated with a rapid return (within 45 min) of lymph flow to base-line levels. These results suggest that hyperpnea increases the pulmonary transvascular filtration rate. Since no changes in vascular pressures or cardiac output were observed, this increase in transvascular filtration is most likely due to a fall in interstitial fluid pressure.
Animals↗
Detection of glycosaminoglycans at the one-nanogram level by 125I-cytochrome c.
The basic protein cytochrome c forms stable ionic complexes with all known glycosaminoglycans. When labeled with 125I, cytochrome c is capable of detecting exceptionally small quantities of glycosaminoglycans. Subsequent to electrophoresis on cellulose acetate strips using pyridine formate buffer at pH 3, followed by ethanol fixation, and treatment with 125I-cytochrome c, all the known glycosaminoglycans are detected at minimum levels of 1 ng/0.25-microliter application. The method can be used for quantification of glycosaminoglycans in other electrophoretic buffer systems also.
Animals↗
Vasodilator therapy for primary pulmonary hypertension.
Explore the source record for details and available documents.
Acetylcholine↗
Respiratory sensations and dyspnea.
Explore the source record for details and available documents.
Affective Symptoms↗
Adaptation to reflex effects of prolonged lung inflation.
Adaptation to the reflex effects of sustained changes in lung volume on inspiratory duration (TI), expiratory duration (TE), and the phrenic neurogram was examined. Test inflations in gallamine-paralyzed dogs anesthetized with pentobarbital sodium were made during a 6-min trial while the animal was not ventilated: 2 min at functional residual capacity (FRC), 2 min at elevated airway pressure, and 2 min back at FRC. The dogs were hyperoxygenated and arterial PCO2 was kept constant by an infusion of tris (hydroxymethyl) aminomethane. The maintained inflations produced minimal changes in TI. On return to FRC, TI was prolonged in proportion to the magnitude of the prior inflation. In contrast, inflation produced marked prolongation of TE, which then adapted back toward preinflation values. On return to FRC, TE shortened initially to values below control. This shortening increased with greater prior lung inflations. The times to reestablish steady-state values upon return to FRC differed for TI (14.8 +/- 4.6 s) and TE (33.8 +/- 12.7 s). The magnitude of the phrenic neurogram at a fixed time from onset of inspiration and its slope were unchanged with inflation. These results indicate that respiratory phase durations are influenced not only by pulmonary afferent input within each respiratory cycle but also by prior vagal afferent activity that engages central processes with long, although different, time constants. Afferent input to the slow central process controlling TI is not gated to only one phase of the respiratory cycle.
Adaptation, Physiological↗
Circulatory adaptation to bimodal respiration in the dipnoan lungfish.
In the dipnoan lungfish, Protopterus aethiopicus, P. annectens, and Lepidosiren paradoxa, the ductus is a short powerful muscular vascular trunk forming a channel for communication between the systemic and pulmonary circulations. In structure, the dipnoan ductus is very similar to the ductus arteriosus (Botalli) in the mammal. Innervation is abundant, consisting of myelinated and nonmyelinated nerve fibers issuing, at least in part, from the vagus. Neurons are present in the adventitia, and numerous nerve profiles, filled with small agranular vesicles, are closely associated with the myocytes, suggesting strong cholinergic control. Perfusion of the ductus in vitro using hypoxic saline causes it to dilate; conversely it is constricted by alpha-agonists. Dopamine and prostaglandin E2 are potent dilators, whereas the beta-agonist, isoproterenol, and acetylcholine are less powerful. A vasomotor segment has been identified on the pulmonary artery (PAVS) close to its junction with the ductus. Its location and structure are similar to the corresponding segment in amphibians and reptiles. It is innervated by endings filled with small clear vesicles. Granular vesicle cells are also present within the adventitia. The PAVS is constricted by acetylcholine. As in amphibians, alpha-agonists and hypoxic saline are without vasomotor effects. Based on the anatomic and physiological observations, a concept of cyclic perfusion of the gas exchangers in Dipnoi is proposed. During the alternation between air breathing (emersion) and apneic phases (immersion), the pattern of the circulation in the lungfish oscillates between that of a tetrapod and a fish.
Animals↗
Passage of uncharged dextrans from blood to lung lymph in awake sheep.
To examine how molecular size alone influences the passage of macromolecules from the pulmonary microcirculation into lymph collected from the caudal mediastinal lymph node of the sheep, we infused polydisperse uncharged [3H]dextrans intravenously at a constant rate over a period of 7.5 h in nine awake sheep with lung lymph fistulas. Lymph and plasma were collected during hours 5.5-7.5 of the infusions, and the [3H]dextrans were separated by molecular sieve chromatography into fractions that ranged from 1.6 to 8.4 nm in effective molecular (Stokes-Einstein) radius. Lymph-to-plasma (L/P) ratios for [3H]dextrans were near 1.0 at 1.6-nm radius, decreased with increasing molecular size, and approached zero at radii above 5.0 nm. We confirmed that these L/P ratios represented steady-state values by extending the duration of the infusion to approximately 30 h in two of the nine sheep and finding that the L/P ratios remained unchanged. These results were consistent with molecular sieving through a homoporous membrane with cylindrical pores of 5.0-nm radius. We also found that the L/P ratio for albumin [0.76 +/- 0.13 (SE)] in five of the same sheep was much higher than that for the [3H]dextran fraction of the same effective molecular radius [0.11 +/- 0.02 (SE)]. These results suggest that the movement of macromolecules from the pulmonary microcirculation into pulmonary lymph collected from the caudal mediastinal node of the sheep is influenced by both molecular size and molecular charge and that, compared with uncharged dextrans, the steady-state passage of anionic endogenous proteins from plasma to lymph is enhanced.
Animals↗
The pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease.
Although it is well known that the pulmonary circulation is altered in patients with pulmonary arterial or venous hypertension, the resultant hemodynamic behavior has not been systematically studied. We undertook to do so in a group of patients with pulmonary hypertension of diverse etiology. We measured pulmonary arterial (PAP) and occlusive wedge pressures and cardiac output at rest (i.e., standing) and during progressive upright treadmill exercise in 51 patients. Forty-two had chronic, stable, cardiac failure secondary to ischemic, myopathic or valvular heart disease and were grouped according to whether their mean PAP was less than (normotensive) or greater than (hypertensive) 19 mm Hg, and nine had pulmonary vascular disease of diverse etiology and were considered separately. In the majority of patients, we found that irrespective of whether the hypertension was arterial or venous in origin or etiology: the mean PAP-flow relationship was linear; pulmonary capillary wedge pressure was greater than or equal to the average closure pressure of the pulmonary vascular bed and could therefore be used as the downstream pressure in calculating pulmonary vascular resistance; and pulmonary vascular resistance declined with exercise. Notable exceptions to the third observation were patients with valvular heart disease or a resting pulmonary vascular resistance greater than 800 dyne-sec-cm-5.
Blood Pressure↗
Glycosaminoglycan biosynthesis in the isolated perfused rat lung.
The suitability of an isolated lung, perfused under carefully monitored conditions, for the study of the biosynthesis of glycosaminoglycans was examined for the rat lung using either [35S]-sulfate or [6-3H]glucosamine. Metabolic and electron-microscopic studies after 3 h of perfusion showed that under the conditions of this study the isolated lung showed no anatomical or metabolic derangements. All glycosaminoglycans normally synthesized in the intact lung were identified. The predominant glycosaminoglycan was heparan sulfate (40% of total). Approximately 14% of the glucosamine incorporated into the glycosaminoglycans was found in hyaluronic acid. Less than 5% of either label was in heparin. The remainder of the synthesized glycosaminoglycans, with the exception of 10% which could not be identified, consisted of the chondroitin sulfates and dermatan sulfate. The relative proportions of the newly synthesized glycosaminoglycans, including the low amounts of heparin, are similar to those found in isolation of endogenous lung glycosaminoglycans. The isolated perfused rat lung appears to be a useful model for the study of glycosaminoglycan biosynthesis by the intact lung.
Animals↗
Exercise testing to evaluate patients with pulmonary vascular disease.
The maximal oxygen uptake and anaerobic threshold can be determined in patients with pulmonary vascular disease from noninvasive gas exchange measurements during progressive exercise. Maximal O2 utilization correlates directly with the maximal level of cardiac output and is inversely proportional to the pulmonary vascular resistance and the level of pulmonary arterial pressure. The accuracy of predicting the hemodynamic profile from noninvasive gas exchange measurements will obviously improve as more such patients are evaluated. Therefore, the determination of VO2 max has the potential of becoming a practical screening technique for detecting and predicting the severity of pulmonary vascular disease.
Adult↗
Heart, lungs, and blood as an integrated system: the alveolar-capillary barrier and the cardiorespiratory apparatus.
The living organism is complex and depends on information transfer for its effective operation. One way to regard the organism is as a biological hierarchy in which each level not only serves a particular, circumscribed function but also contributes in an important way to the integrated performance of the organism as a whole. Two levels in the organization of biological functions are discussed to illustrate the principle of biological hierarchy: a subsidiary role, as exemplified by the role of the lungs in water and macromolecular exchange, and a primary function, as typified by the integrated performance of the cardiorespiratory apparatus in accord with the metabolic needs of the whole body. This hierarchical approach not only preserves the perspective for appreciating the coordinated behavior of the normal individual but also provides a vantage for assessing derangements produced by disease at any level in the biological hierarchy.
Blood↗
Pulmonary mechanoreceptors in the dipnoi lungfish Protopterus and Lepidosiren.
Pulmonary mechanoreceptors in the dipnoi lungfish Protopterus aethiopicus and Lepidosiren paradoxa were identified and characterized both in vivo and in vitro. Both slowly adapting receptors (SAR) and rapidly adapting receptors (RAR) were found, with the majority of receptors being of the slowly adapting type. The SAR discharged during inflation once their threshold volume was exceeded, and this activity persisted during prolonged lung inflation. For most of the SAR, interaction between the rate of inflation and lung volume was involved in setting the firing rate of the receptor. Increase in intrapulmonary carbon dioxide partial pressure decreased the activity of the SAR during sustained inflation at a constant intrapulmonary pressure. The RAR also discharged during inflation once the threshold volume was exceeded. However, in contrast to the SAR, the RAR became silent within 1.5 - 15 s after the end of inflation. The activity of these receptors during inflation was influenced predominantly by the rate and influenced little by the volume of inflation. According to these observations, the behavior of lungfish pulmonary mechanoreceptors closely resembles that of pulmonary mechanoreceptors in amphibians but differs from that of mechanoreceptors in the swim bladder of teleosts.
Acclimatization↗
Effects of hypercapnia and hypoxia on abdominal expiratory nerve activity.
We examined the effects of progressive hypercapnia and hypoxia on the efferent neural activity in a whole abdominal expiratory nerve (medial branch of the cranial iliohypogastric nerve (L1) in anesthetized, paralyzed dogs. To eliminate effects of phasic lung and chest-wall movements on expiratory activity, studies were performed in the absence of breathing movements. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in the paralyzed animals by allowing 3-5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer at a predetermined rate. To quantify abdominal expiratory activity, mean abdominal nerve activity in a nerve burst was computed by integrating the abdominal neurogram and dividing by the duration of the nerve burst. Hypercapnia and hypoxia both increased mean abdominal nerve activity and decreased expiratory duration. In contrast to the ramplike phrenic neurogram, the abdominal neurogram consisted of three phases: an initial rising phase, a plateau phase in which abdominal nerve activity was approximately constant, and a terminal declining phase in which the activity returned to the base-line level. The height of this plateau phase and the rates of rise and decline of abdominal nerve activity all increased with increasing hypercapnia and hypoxia. We conclude that, with proprioceptive inputs constant, both hypercapnia and hypoxia are excitatory to abdominal expiratory neural activity.
Abdomen↗
Comparative biology of the lung.
Explore the source record for details and available documents.
Adaptation, Biological↗