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Biomedical subjects

R M Effros

Publications and source records attributed to R M Effros.

At least 19 recordsLinked to original sources
PubMed2000

Response of the lungs to aspiration.

Aspiration of acid from the stomach and water from the mouth can cause significant lung injury. Animal experiments suggest that acid entering the lungs is normally neutralized by bicarbonate derived from the plasma. It is hypothesized that this process may be impaired in patients with cystic fibrosis and that some of the airway injury that they experience may be related to this defect. This disease is characterized by abnormalities in the cystic fibrosis transmembrane conductance regulator, which normally conducts bicarbonate and chloride exchange. Evidence is discussed regarding the role of water channels (aquaporins) in transporting water from the airspaces into the vasculature.

Aquaporins↗
PubMed2000

Gastric tonometry.

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Carbon Dioxide↗
PubMed1999

Airway synthesis of 20-hydroxyeicosatetraenoic acid: metabolism by cyclooxygenase to a bronchodilator.

Rabbit airway tissue is a particularly rich source of cytochrome P-4504A protein, but very little information regarding the effect(s) of 20-hydroxyeicosatetraenoic acid (20-HETE) on bronchial tone is available. Our studies examined the response of rabbit bronchial rings to 20-HETE and the metabolism of arachidonic acid and 20-HETE from airway microsomes. 20-HETE (10(-8) to 10(-6) M) produced a concentration-dependent relaxation of bronchial rings precontracted with KCl or histamine but not with carbachol. Relaxation to 20-HETE was blocked by indomethacin or epithelium removal, consistent with the conversion of 20-HETE to a bronchial relaxant by epithelial cyclooxygenase. A cyclooxygenase product of 20-HETE also elicited relaxation of bronchial rings. [14C]arachidonic acid was converted by airway microsomes to products that comigrated with authentic 20-HETE (confirmed by gas chromatography-mass spectrometry as 19- and 20-HETE) and to unidentified polar metabolites. [3H]20-HETE was metabolized to indomethacin-inhibitable products. These data suggest that 20-HETE is an endogenous product of rabbit airway tissue and may modulate airway resistance in a cyclooxygenase-dependent manner.

Animals↗
PubMed1998

Human cloning.

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Cloning, Organism↗
PubMed1998

Stop-flow studies of distribution of filtration in rat lungs.

The stop-flow approach was used to investigate where filtration occurs in the pulmonary vasculature after elevation of left atrial pressure and aspiration of HCl. Rat lungs were perfused for 11 min at zero left atrial pressures, and then flow was stopped for 10 min and left atrial pressures were increased to 20 cmH2O. Thereafter, 3HOH was instilled into the air spaces, and the pulmonary vasculature was flushed by perfusing it from the pulmonary artery to left atrium (anterograde flush) or in the opposite direction (retrograde flush). Increases in fluorescein isothiocyanate (FITC)-dextran (molecular weight 2,000,000) indicated filtration, and these preceded increases in 3HOH after anterograde but not retrograde flushes. This suggests that some filtration occurred through vessels that were relatively venous compared with those through which 3HOH exchange had occurred. Filtration increased fivefold after instillation of 0.1 N HCl in isotonic saline into the air spaces before perfusion. Increases in Evans blue-labeled albumin concentrations were < 40% those of FITC-dextran, indicating loss from the vasculature, but increases in unlabeled albumin and FITC-albumin were comparable.

Animals↗
PubMed1998

Stop-flow studies of solute uptake in rat lungs.

Stop-flow studies were used to characterize solute uptake in isolated rat lungs. These lungs were perfused at 8 or 34 ml/min for 10-28 s with solutions containing 125I-albumin and two or more of the following diffusible indicators: [3H]mannitol, [14C]urea, 3HOH, 201Tl+, or 86Rb+. After this loading period, flow was stopped for 10-300 s and then resumed to flush out the perfusate that remained in the pulmonary vasculature during the stop interval. Concentrations of 201Tl+ and 86Rb+ in the venous outflow decreased after the stop interval, indicating uptake from exchange vessels during the stop interval. The amount of these K+ analogs lost from the circulation during the stop interval was greater when the intervals were longer. However, losses of 201T1+ at 90 s approached those at 300 s. Because extraction continued after the vasculature had been flushed, vascular levels had presumably fallen to negligible levels during the stop interval. By 90 s of stop flow the vascular volume that was cleared of 201T1+ averaged 0.657 +/- 0.034 (SE) ml in the experiments perfused at 8 ml/min and 0.629 +/- 0.108 ml in those perfused at 34 ml/min. Increases in perfusate K+ decreased the cleared volumes of 201T1+ and 86Rb+. Uptake of [3H]mannitol, [14C]urea, and 3HOH during the stop intervals was observed only when the lungs were loaded at high flow for short intervals. Decreases in 201T1+ and 86Rb+ concentrations in the pulmonary outflow can be used to identify the fraction of the collected samples that were within exchange vessels of the lung during the stop interval and may help determine the distribution of solute and water exchange along the pulmonary vasculature.

Animals↗
PubMed1998

Tissue sources of cytochrome P450 4A and 20-HETE synthesis in rabbit lungs.

We previously reported that 20-hydroxyeicosatetraenoic acid (20-HETE) is an endogenous cytochrome P450 (cP450) 4A metabolite of arachidonic acid (AA) in human lung tissue, and is a potent cyclooxygenase-dependent vasodilator of isolated pulmonary arteries. In the present investigations, we identified sources of cP450 4A immunospecific protein, messenger RNA (mRNA), and 20-HETE synthesis in rabbit lungs. Microsomes of peripheral lung tissue, airways, small and large vessels, and lysates of alveolar macrophages all express proteins of approximately 50 kD which cross-reacted with a primary antibody raised against rat liver cP450 4A1. Peripheral lung tissue, small and large pulmonary arteries, airways, and isolated vascular smooth muscle cells from small pulmonary arteries produced 20-HETE when incubated with AA. Expression of cP450 4A6/4A7 mRNA was readily detectable by reverse transcription-polymerase chain reaction using isoform-specific probes and 5 microg total RNA extracted from microdissected small pulmonary arteries. These data demonstrate that small pulmonary arteries express cP450 4A proteins and vascular smooth muscle cells derived from these arteries synthesize 20-HETE. Furthermore, cP450 4A appears to be widely distributed in rabbit tissue, raising the possibility that 20-HETE generated from nonvascular tissue could serve as a paracrine factor in the pulmonary circulation.

Animals↗
PubMed1997

Human pulmonary arteries dilate to 20-HETE, an endogenous eicosanoid of lung tissue.

We investigated the effect of 20-hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite of the cytochrome P-450 (cP450) 4A pathway, on human pulmonary arterial tone. 20-HETE elicited a dose-dependent and indomethacin-inhibitable vasodilation of isolated small pulmonary arteries. Whole lung microsomes metabolized [24C]arachidonic acid into 20-HETE and a variety of leukotrienes, epoxyeicosatrienoic acids, and prostanoids. Indomethacin blocked formation of prostanoids without effects on the conversion of arachidonate into 20-HETE, 20-HETE was converted by lung microsomes into prostanoids, raising the possibility that 20-HETE may be metabolized by cyclooxygenase enzymes in vascular tissue to a vasodilatory compound. Western blots probed with a polyclonal antibody to cP450 4A identified a protein of approximately 50 kDa immunologically similar to the cP450 4A in rat liver. We conclude that small arteries from human lungs dilate upon exposure to 20-HETE in a cyclooxygenase-dependent manner and that the proteins and enzymatic activity required to synthesize this product are present in lungs. Our observations suggest that cP450 enzyme products could be endogenous modulators of pulmonary vascular tone.

Animals↗
PubMed1997

Water transport and the distribution of aquaporin-1 in pulmonary air spaces.

Recent evidence suggests that water transport between the pulmonary vasculature and air spaces can be inhibited by HgCl2, an agent that inhibits water channels (aquaporin-1 and -5) of cell membranes. In the present study of isolated rat lungs, clearances of labeled (3HOH) and unlabeled water were compared after instillation of hypotonic or hypertonic solutions into the air spaces or injection of a hypotonic bolus into the pulmonary artery. The clearance of 3HOH between the air spaces and perfusate after intratracheal instillation and from the vasculature to the tissues after pulmonary arterial injections was invariably greater than that of unlabeled water, indicating that osmotically driven transport of water is limited by permeability of the tissue barriers rather than the rate of perfusion. Exposure to 0.5 mM HgCl2 in the perfusate and air-space solution reduced the product of the filtration coefficient and surface area (PfS) of water from the air spaces to the perfusate by 28% after instillation of water into the trachea. In contrast, perfusion of 0.5 mM HgCl2 in air-filled lungs reduced PfS of the endothelium by 86% after injections into the pulmonary artery, suggesting that much of the action of this inhibitor is on the endothelial surfaces. Confocal laser scanning microscopy demonstrated that aquaporin-1 is on mouse pulmonary endothelium. No aquaporin-1 was found on alveolar type I cells with immunogold transmission electron microscopy, but small amounts were present on some type II cells.

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

Responses to pressure and vasoactive agents by isolated pulmonary arteries from monocrotaline-treated rats.

Intralobar and side branch pulmonary arteries removed from rats 7, 14, and 21 days after injection with monocrotaline (MCT) were cannulated and pressurized, and their responses to potassium chloride, norepinephrine, acetylcholine, and angiotensin II were measured. Static pressure-diameter curves were also performed, and arterial distensibility was calculated. Arteries from all three MCT-treated groups showed reduced responses to potassium chloride and angiotensin II compared with control arteries (P < 0.05). The norepinephrine response was significantly reduced in arteries from the 14- and 21-day groups (P < 0.05). Dilations in response to acetylcholine were similar in arteries from the control and 7-day groups but were reduced compared with those in control vessels from the 14- and 21-day groups (P < 0.05). Compared with control values, the slopes of the pressure-diameter curves and the arterial distensibility decreased significantly with time after MCT treatment (P < 0.05). Values for arterial distensibilities obtained in the isolated pulmonary arteries support the theory that structural changes that occur as a result of MCT administration contribute to vessel stiffness. The acetylcholine-induced dilation of vessels from MCT-treated rats indicates that endothelium-derived factors are still produced, but diminished vasodilation coupled with decreased distensibilities after MCT suggest that abnormal vascular remodeling rather than a change in agonist sensitivity may be responsible for the reduced responsiveness seen in these arteries.

Acetylcholine↗
PubMed1994

Reduction and uptake of methylene blue from rat air spaces.

The use of methylene blue (MB) to estimate dilution of epithelial lining fluid, which occurs during bronchoalveolar lavage (BAL), is complicated by loss of this redox dye from the air spaces. The rate of MB uptake from the air spaces of isolated rat lungs and the effects of oxidation and reduction on this process were investigated in this study. Movement of MB from the air spaces to perfusate was compared with the corresponding transport of 125I-labeled albumin, [14C]-dextran, 99mTc-labeled diethylenetriaminepentaacetate, [3H]-sucrose, and 3H2O. By the end of 2 min, MB concentrations in the BAL had fallen by 58 +/- 4% (SE; n = 11) and 3H2O by 78 +/- 2% (n = 13), whereas concentrations of the other indicators decreased by approximately 6%. All but 10% of the 3H2O lost from the air spaces was found in the perfusate, whereas 19% of the lost MB was not recovered in the perfusate, suggesting retention of MB in the pulmonary tissues. Absorption of MB from the air spaces was slowed by 20% when the lungs were left unperfused, and absorption was accelerated threefold by reduction of MB to leukomethylene blue with Na2S2O4. In contrast, MB losses from the air space were slowed by the oxidizing agent K3Fe(CN)6 and by addition of superoxide dismutase or ascorbic oxidase. It is therefore possible that ascorbic acid and O2- entering the air spaces reduce MB to the uncharged leuko form. Lowering the pH of the BAL fluid to 3.5 also slowed MB reabsorption. This suggests that acid aspiration may stimulate release of oxidants into the air spaces.

Animals↗
PubMed1994

Continuous measurements of changes in pulmonary capillary surface area with 201Tl infusions.

The impact of physiological and pathological processes on metabolism and transport of a variety of substances traversing the pulmonary vasculature depends in part on the capillary surface area available for exchange, and a reliable method for detecting changes in this parameter is needed. In this study, a continuous-infusion approach was used to investigate the response of the pulmonary capillary surface area to increases in flow and left atrial pressure. Isolated rat lungs were perfused with an acellular perfusion solution containing 125I-labeled albumin (an intravascular indicator) and 201Tl, a K+ analogue which is concentrated within lung cells. The extraction of 201Tl from the perfusate was 61% greater at low flow (8.5 ml/min) than at high flow (26 ml/min), and rapid changes in extraction were observed when flow was altered. In contrast, the permeability-surface area product was 76% greater when lungs were perfused at high flow than at low flow, suggesting comparable increases in pulmonary capillary surface area in these zone 2 lungs (airway pressure = 5 cmH2O, left atrial pressure < 0 cmH2O). In a second group of experiments, increases in left atrial pressure to 14 cmH2O (zone 3 lungs) at a constant flow of 8.5 ml/min increased the permeability-surface area product by only 18% despite increases in average intravascular pressure that were at least as high as those associated with high perfusion rates. 201Tl infusions provide a useful method for detecting and quantifying changes in pulmonary capillary surface area.

Animals↗
PubMed1994

Hydroxyl radicals are formed in the rat lung after asbestos instillation in vivo.

The hydroxyl radical (.OH) has been implicated as a cause of lung injury following asbestos exposure. However, despite in vitro evidence associating asbestos with .OH production, there has been no demonstration of such generation in vivo. We tested the hypothesis that .OH is formed in the lungs of rats exposed to asbestos in vivo by using salicylate as a free radical trap. Asbestos was instilled intratracheally, and control rats were sham-exposed. Six to seven days after exposure, the rats were given salicylate, the lungs were isolated, and salicylate hydroxylation products (2,3- and 2,5-dihydroxybenzoic acid), reflecting .OH production, were measured. There was significantly more 2,3-dihydroxybenzoic acid in asbestos-exposed lungs compared with control lungs (2.32 +/- 0.360 nmol/lung versus 0.292 +/- 0.125, respectively, P < 0.001) and 2,5-dihydroxybenzoic acid (9.69 +/- 1.65 nmol/lung versus 2.63 +/- 0.274, respectively, P < 0.001). To demonstrate that the dihydroxybenzoic acid was actually formed in the lungs, the lungs from asbestos-exposed and control rats were isolated and perfused with either salicylate or 2,3-dihydroxybenzoic acid. In the lungs perfused with salicylate, 2,3- and 2,5-dihydroxybenzoic acids were detectable only in asbestos-exposed lungs. In the isolated lungs perfused with 2,3-dihydroxybenzoic acid, there was no significant difference in 2,3-dihydroxybenzoic acid between asbestos-exposed and control lungs. We conclude that asbestos stimulates .OH production in lungs in vivo.

Animals↗