Alveolar and lung liquid clearance in anesthetized rabbits

Alveolar and lung liquid clearance were studied over 8 h in intact anesthetized ventilated rabbits by instillation of either isosmolar Ringer lactate (2 ml/kg) or autologous plasma (2 or 3 ml/kg) into one lower lobe. The half time for lung liquid clearance of the isosmolar Ringer lactate was 3.3 h and that for plasma clearance was 6 h. In the plasma experiments, the alveolar protein concentration after 1 h was 5.2 +/- 0.8 g/dl, which was significantly greater than the initial instilled protein concentration of 4.3 +/- 0.7 g/dl (P less than 0.05). Thus alveolar protein concentration increased by 21 +/- 12% over 1 h, which matched clearance from the entire lung of 19 +/- 11% of the instilled volume. Overall the rate of alveolar and lung liquid clearance in rabbits was significantly faster than in prior studies in dogs and sheep. The fast alveolar liquid clearance rate in rabbits was not due to higher endogenous catecholamine release, because intravenous and alveolar (5 x 10(-5) M) propranolol did not slow the clearance. Also, beta-adrenergic therapy with alveolar terbutaline (10(-5) or 10(-4) M) did not increase the alveolar or lung liquid clearance rates. Phloridzin (10(-3) M) did not slow alveolar liquid clearance. However, amiloride (10(-4) M) inhibited 75% of the basal alveolar liquid clearance in rabbits, thus providing evidence that alveolar liquid clearance in rabbits depends primarily on sodium-dependent transport. This rabbit study provides further evidence for important species differences in the basal rates of alveolar liquid and solute clearance as well as the response to beta-adrenergic agonists and ion transport inhibitors.     

Alveolar liquid and protein clearance from normal dog lungs

To determine whether liquid and protein clearance from the air spaces and lungs of anesthetized and unanesthetized dogs is the same as in sheep, we quantified these variables at three different time periods (4, 8, and 12 h) by instilling heparinized plasma (3 ml/kg) labeled with 125I-albumin into one lower lobe. Protein clearance, measured from the residual 125I-albumin in the lung homogenate, was slow and monoexponential (approximately 1%/h), similar to our previous data for protein clearance from the lungs in sheep. Lung liquid clearance in dogs, however, was 50% less than in previous experiments in sheep. Residual lung liquid (as percent of instilled) was 88.7 +/- 7.0 at 4 h, 70.5 +/- 9.1 at 8 h, and 64.0 +/- 5.8 at 12 h. At each time period, alveolar protein concentration increased by 0.6 +/- 0.4 g/dl at 4 h, 1.3 +/- 1.2 g/dl at 8 h, and 2.1 +/- 0.8 g/dl at 12 h. This increase in alveolar protein concentration was proportional to the volume of liquid removed from the lungs. beta-Adrenergic agonist therapy with terbutaline (10(-5) M mixed with the instilled plasma) doubled the volume of liquid cleared from the lungs over 4 h, and the alveolar protein concentration increased proportionally. However, lung liquid clearance in dogs that were treated with beta-agonists was proportionally (50%) less than in sheep treated with beta-agonists. The slower liquid clearance in dogs compared with sheep cannot be explained by differences in hemodynamics, pulmonary blood flow, anesthesia, mode of ventilation, or alveolar surface area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Compounds that increase cAMP prevent ischemia-reperfusion pulmonary capillary injury.

This study evaluated the physiological effects of compounds that increase adenosine 3',5'-cyclic monophosphate (cAMP) on changes in pulmonary capillary permeability and vascular resistance induced by ischemia-reperfusion (I-R) in isolated blood-perfused rabbit lungs. cAMP was elevated by 1) beta-adrenergic stimulation with isoproterenol (ISO, 10(-5) M), 2) post-beta-receptor stimulation of adenylate cyclase with forskolin (FSK, 10(-5) M), 3) and dibutyryl cAMP (DBcAMP, 1 mM), a cAMP analogue. Vascular permeability was assessed by determining the capillary filtration coefficient (Kf,c), and capillary pressure was measured using the double occlusion technique. The total, arterial, and venous vascular resistances were calculated from measured pulmonary arterial, venous, and capillary pressures and blood flow. Reperfusion after 2 h of ischemia significantly (P less than 0.05) increased Kf,c (from 0.115 +/- 0.028 to 0.224 +/- 0.040 ml.min-1.cmH2O-1.100 g-1). These I-R-induced changes in capillary permeability were prevented when ISO, FSK, or DBcAMP was added to the perfusate at reperfusion (0.110 +/- 0.022 and 0.103 +/- 0.021, 0.123 +/- 0.029 and 0.164 +/- 0.024, and 0.153 +/- 0.030 and 0.170 +/- 0.027 ml.min-1.cmH2O-1.100 g-1, respectively). I-R significantly increased total, arterial, and venous vascular resistances. These increases in vascular resistance were also blocked by ISO, FSK, and DBcAMP. These data suggest that beta-adrenergic stimulation, post-beta-receptor activation of adenylate cyclase, and DBcAMP prevent the changes in pulmonary vascular permeability and vascular resistances caused by I-R in isolated rabbit lungs through a mechanism involving an increase in intracellular levels of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dibutyryl cAMP induces a gestation-dependent absorption of fetal lung liquid

The maturation of the adenosine 3',5'-cyclic monophosphate-(cAMP) dependent pathway controlling fetal lung liquid secretion was examined in experiments in which the lungs of chronically catheterized fetal lambs (123-141 days gestational age) were exposed to dibutyryl cAMP (DBcAMP, 10(-4) M). The effect of DBcAMP was markedly gestation dependent, with the greatest effect observed in the most mature fetuses. In immature fetuses (less than 130 days, mean age 125 days) DBcAMP caused slowing of secretion, with maximal effect at 5 h. With increasing maturity the effect of DBcAMP was more pronounced and occurred earlier so that in mature fetuses (mean age 140 days) lung liquid absorption took place, with maximal effect at 2 h. Changes in lung liquid volume flow induced by DBcAMP could be blocked by addition of 10(-4) M amiloride to lung liquid. It is concluded that 1) DBcAMP induces a change in lung liquid secretion that, like epinephrine, is mediated via an increase in Na+ permeability of the apical membrane of the lung epithelium and 2) the rate-limiting step in the maturation of this process must lie beyond the generation of intracellular cAMP.     

Increased pulmonary vascular filtration pressure does not alter lung liquid secretion in fetal sheep.

The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.     

Effects of dibutyryl cAMP on pulmonary air embolism-induced lung injury in awake sheep

To assess the role of intracellular adenosine 3',5'-cyclic monophosphate (cAMP), we tested the effects of dibutyryl cAMP (DBcAMP), an analogue of cAMP, on lung injury induced by pulmonary air embolism in awake sheep with chronic lung lymph fistula. We infused air (1.23 ml/min) in the pulmonary artery for 2 h in untreated control sheep. In DBcAMP-pretreated sheep DBcAMP was infused (1 mg/kg bolus and 0.02 mg.kg-1.min-1 constantly for 5 h); after 1 h from beginning of DBcAMP administration the air infusion was started. After the air infusion, pulmonary arterial pressure (Ppa) and lung lymph flow rate (Qlym) significantly increased in both groups. DBcAMP-pretreated sheep showed significantly lower responses in Qlym (2.7 X base line) compared with untreated control sheep (4.6 X base line); however, Ppa, left atrial pressure, and lung lymph-to-plasma protein concentration ratio were not significantly different between the two groups. Although plasma and lung lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations increased significantly during the air infusion, DBcAMP-pretreated sheep showed significantly lower responses. Thus DBcAMP infusion attenuated pulmonary microvascular permeability induced by air embolism. We conclude that pulmonary vascular permeability is in part controlled by the intracellular cAMP level.     

Reversal of increased microvascular permeability associated with ischemia-reperfusion: role of cAMP.

Ischemia-reperfusion (IR) is a form of oxidant injury known to increase microvascular permeability in the lung. Agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) levels have been shown to have beneficial effects in several models of oxidant lung injury associated with increased microvascular permeability. We investigated the role of adenylate cyclase activation with isoproterenol (ISO) or forskolin (FSK) in reversing the increased microvascular permeability associated with IR. ISO or FSK administered after 45 min of ischemia and 46 min of reperfusion caused a reduction in the capillary filtration coefficient (Kfc) from 1.25 +/- 0.13 to 0.53 +/- 0.08 and 0.55 +/- 0.10 ml.min-1.cmH2O-1.100 g tissue-1, respectively, at 90 min of reperfusion. This reduction in Kfc was accompanied by a rise in perfusate cAMP levels from 16.5 +/- 4.9 and 31.2 +/- 11.9 pmol/ml at 45 min of reperfusion to 444.2 +/- 147.8 and 276.1 +/- 91.0 pmol/ml at 105 min of reperfusion in lungs treated with ISO or FSK, respectively, at 46 min of reperfusion. Dibutyryl cAMP (DBcAMP), a membrane-permeable cAMP analogue, mimicked the permeability effect by reducing Kfc to 0.67 +/- 0.15 at 90 min of reperfusion. Significant hemodynamic changes occurred but were small and cannot explain the observed effect on Kfc. Photomicrographs from lungs treated with ISO or FSK revealed a reversal of the morphological manifestations of increased microvascular permeability. We conclude that the increased microvascular permeability associated with IR can be reversed by ISO, FSK, and DBcAMP and that cAMP produced by the lung contributes to the observed reversal.     

Inhibition of potassium uptake by low concentrations of norepinephrine and dibutyryl cyclic AMP.

(1) The inhibition of potassium uptake by low concentration of norepinephrine (3 X 10-8 M) and of dibutyryl cyclic AMP (DBcAMP, 10 minus5 M) was studied in cardiac Purkyn? fibres. (2) The inhibitory action of DBcAMP on K uptake was abolished by the alpha blocker phentolamine. (3) Norepinephrine alone decreased K uptake and such inhibition was somewhat larger when DBcAMP was added. DBcAMP alone caused the usual decrease in K uptake but addition of norepinephrine abolished it. (4) The inhibition caused by norepinephrine reduced the increase in uptake caused by a high concentration (10 minus 3 M) of DBcAMP. (5) The inhibitory effect of norepinephrine was reversed in the presence of high concentration of magnesium (5.25 mM). (6) The inhibitory effect of norepinephrine was reversed by aminophylline and abolished by caffeine. (7) The inhibitory action of norepinephrine and BCcAMP was reversed or abolished, respectively, by imidazole. (8) It is concluded that the inhibition of potassium uptake by low concentration of DBcAMP is mediated by an alpha receptor mechanism and that possibly the "receptors" for this effect of norepinephrine and DBcAMP are located at different sites. Also it appears that DBcAMP may be acting at the membrane and that the action of methylxanthines and imidazole is not necessarily mediated only by a modification of phosphodiesterase activity.     

Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h

We studied the rate, the routes, and the mechanisms for protein clearance from the air spaces and lungs of 20 unanesthetized sheep over 144 h. We instilled 100 ml of autologous serum labeled with 125I-albumin into one lung. At the end of 24, 48, 96, or 144 h, the lungs were removed and the residual native protein and 125I-albumin in the air spaces were determined by bronchoalveolar lavage. Also the fraction of the instilled 125I-albumin remaining in the rest of the lung was measured in the lung homogenate. Clearance of the 125I-albumin from the lung into the plasma, lymph, thyroid, urine, and feces was also determined. The removal of both the 125I-albumin and the native protein from the air spaces was slow, following a monoexponential decline. The removal rate of the 125I-albumin from the air spaces was slightly but significantly faster (1.6%/h) than the clearance rate of the native protein (0.9%/h). Clearance of the 125I-albumin from the lung also followed a slow monoexponential decline at a rate of 1.4%/h. At all time periods, 75% of the 125I-albumin remaining in the lung was located in the air spaces, thus indicating that the pulmonary epithelium is the principal barrier to protein clearance from the normal lung. Macrophages appeared to play a minor role in alveolar protein clearance because the quantity of 125I-albumin present in the phagocytic cells in the air spaces was less than 1% of the instilled 125I-albumin at all time periods. However, macrophages may play some role in protein clearance after 48 h because we visualized phagolysosomes in macrophages, and there was an increase in free iodine in lung lavage, urine, thyroid, and feces after 48 h. However, gel electrophoretic studies showed that most of the 125I-albumin was cleared from the lung as an intact molecule, although only 24.7 +/- 4.7% of the 125I-albumin was cleared by the lymphatics.     

Ion transport regulation of lung liquid secretion in foetal lambs.

To test the hypothesis that liquid formation in the foetal lung reflects the balance between Cl- secretion and Na+ absorption by the respiratory tract epithelium, we studied the independent and combined effects of selective ion transport inhibitors on basal production of lung liquid in foetal lambs. We prepared 19 foetal lambs (gestation 125 +/- 4, term = 147 days) with chronic indwelling catheters for subsequent measurement of luminal liquid production over time (JV). Using an impermeant tracer technique, we measured JV before and after tracheal instillation of 2 different inhibitors of ion transport: bumetanide, a Na(+)-K(+)-2Cl- co-transport inhibitor, and amiloride, a Na+ transport inhibitor. In 7 foetuses we sequentially added bumetanide (10(-4) M) and 2 different concentrations of amiloride (10(-6) M, 10(-4) M) to the liquid within the lung lumen. After we gave bumetanide, JV decreased from 12 +/- 4 ml/h to 0 +/- 5 ml/h and subsequently increased during the 2 periods of amiloride exposure (10(-6) M: 6 +/- 5 ml/h; 10(-4) M: 7 +/- 7 ml/h). In 5 control studies we gave bumetanide, followed by only amiloride vehicle. JV for all time periods in the control studies was similar to the experimental group, demonstrating no effect of amiloride. In 5 foetuses we administered the 2 concentrations of amiloride before bumetanide. There was no change in JV with either concentration of amiloride (baseline: 13 +/- 2 ml/h; 10(-6) M amiloride: 15 +/- 5 ml/h; 10(-4) M amiloride: 13 +/- 6 ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclic AMP suppresses expression of v-rasH oncogene linked to the mouse mammary tumor virus promoter

Clone 433.3 of NIH 3T3 cells is a stable carrier of the MMTV LTR:v-rasH chimeric DNA. Only in the presence of dexamethasone (a synthetic glucocorticoid), 433.3 cells exhibit an induced level of p21 transforming protein and phenotypic transformation. N6,O2'-dibutyryl cAMP (DBcAMP) antagonized the effect of dexamethasone in a time - and concentration - dependent manner. DBcAMP (5 X 10(-4)M) added 18 hr prior to the addition of dexamethasone (10(-7)M) almost completely blocked the hormone effect: cells contained levels of p21 20% of that in the cells treated with dexamethasone alone, and formed flat, contact inhibited monolayers. On the basis of these results together with our previous data on mammary carcinomas in vivo, we postulate that cAMP may be an intracellular suppressor acting at a regulatory locus of both cellular and viral ras genes.     

Contribution of amiloride-insensitive pathways to alveolar fluid clearance in adult rats.

The contributions of amiloride-sensitive and -insensitive fractions of alveolar fluid clearance in adult ventilated rats were studied under control conditions and after beta-adrenergic stimulation. Rats were instilled with a 5% albumin solution containing terbutaline (10(-4) M) or dibutyryl-cGMP (DBcGMP; 10(-4) M) with or without the cyclic nucleotide-gated cation channel inhibitor l-cis-diltiazem (10(-3) M) and/or amiloride (10(-3) M). Alveolar fluid clearance over 1 h was 18 +/- 2% in controls. In controls, amiloride inhibited 46 +/- 15% of alveolar fluid clearance, whereas l-cis-diltiazem had no inhibitory effect. Terbutaline and DBcGMP stimulated alveolar fluid clearance by 85 +/- 3 and 36 +/- 5%, respectively. Amiloride and l-cis-diltiazem inhibited nearly equal fractions of terbutaline-stimulated alveolar fluid clearance when given alone. Amiloride and l-cis-diltiazem given together inhibited a significantly larger fraction of alveolar fluid clearance in terbutaline-stimulated rats and in DBcGMP-stimulated rats. Based on these data, terbutaline stimulation recruited both amiloride-sensitive and l-cis-diltiazem-sensitive pathways. In contrast, DBcGMP mainly recruited l-cis-diltiazem-sensitive pathways. Therefore, the amiloride-insensitive fraction of Na+-driven alveolar fluid clearance may be partly mediated through cyclic nucleotide-gated cation channels and activated by an increase in intracellular cGMP.     

Clearance of different-sized proteins from the alveolar space in humans and rabbits.

Investigation of the clearance of proteins from the air spaces is important for an understanding of the resolution of pulmonary edema and also because of current interest in delivery of therapeutic peptides via the distal air spaces. Few experimental studies have examined the size dependence for alveolar clearance of large macromolecules; there have been no human studies. In anesthetized rabbits, we measured clearance of cyanocobalamin and different-sized human proteins instilled into the air spaces. After 8 h, the amounts of instilled tracer recovered in the lungs were [57Co]cyanocobalamin, 19.4 +/- 3.0% (Stokes radius 0.65 nm); 125I-labeled insulin, 64.6 +/- 3.9% (1.2 nm); 131I-labeled albumin, 87.0 +/- 4.0% (3.5 nm); and 125I-labeled immunoglobulin G, 91.8 +/- 3.3% (5.5 nm) (P < 0.05). Sieving of different-sized proteins occurred across the alveolar epithelial barrier because tracer concentrations in air space lavage fluid after 8 h were decreased more for the smaller tracers than the larger ones. Size selectivity for alveolar protein clearance in humans with resolving alveolar edema was investigated by measuring the changes in albumin and total protein concentration. The fraction of total protein concentration made up of albumin was greater in the edema fluid than in the plasma initially. The albumin fraction decreased with time in 9 of 10 patients with resolving edema, from 0.62 +/- 0.2 to 0.58 +/- 0.10 (P < 0.05) after 10 +/- 5 h. Thus both rabbit studies and human studies provide evidence for size-dependent clearance of protein from the air spaces of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term clearance of liquid and protein from the lungs of unanesthetized sheep

We measured the removal of 100 ml of autologous serum from the air spaces and lungs of unanesthetized, spontaneously breathing sheep at 4, 12, and 24 h. In the first 4 h, there was a rapid clearance of the liquid volume (8.3%/h), similar to our results in anesthetized ventilated sheep (Matthay et al., J. Appl. Physiol. 53: 96-104, 1982). However, liquid removal progressively slowed to 3.3 and 1.4%/h at 12 and 24 h, respectively. In contrast, protein clearance (as measured by 125I-albumin instilled with the serum) was monoexponential and slow (1%/h). The slowing of liquid clearance appears to be a function of the rising protein osmotic pressure of the residual protein in the air spaces (protein concentration doubled in 24 h). Because protein solutions are chemotactic for neutrophils, we quantified the movement of liquid from the extracellular space into the alveolar compartment with a plasma protein tracer (131I-albumin), so that our final calculation of alveolar liquid clearance would take into account bidirectional movement of liquid across the alveolar barrier. The corrected values for net liquid clearance are slightly faster (less than 10% of the instilled volume).     

Alveolar fluid reabsorption is impaired by increased left atrial pressures in rats

Cardiogenic pulmonary edema results from increased hydrostatic pressures across the pulmonary circulation. We studied active Na(+) transport and alveolar fluid reabsorption in isolated perfused rat lungs exposed to increasing levels of left atrial pressure (LAP; 0--20 cmH(2)O) for 60 min. Active Na(+) transport and fluid reabsorption did not change when LAP was increased to 5 and 10 cmH(2)O compared with that in the control group (0 cmH(2)O; 0.50 +/- 0.02 ml/h). However, alveolar fluid reabsorption decreased by approximately 50% in rat lungs in which the LAP was raised to 15 cmH(2)O (0.25 +/- 0.03 ml/h). The passive movement of small solutes ((22)Na(+) and [(3)H]mannitol) and large solutes (FITC-albumin) increased progressively in rats exposed to higher LAP. There was no significant edema in lungs with a LAP of 15 cmH(2)O when all active Na(+) transport was inhibited by hypothermia or amiloride (10(-4) M) and ouabain (5 x 10(-4) M). However, when LAP was increased to 20 cmH(2)O, there was a significant influx of fluid (-0.69 +/- 0.10 ml/h), precluding the ability to assess the rate of fluid reabsorption. In additional studies, LAP was decreased from 15 to 0 cmH(2)O in the second and third hours of the experimental protocol, which resulted in normalization of lung permeability to solutes and alveolar fluid reabsorption. These data suggest that in an increased LAP model, the changes in clearance and permeability are transient, reversible, and directly related to high pulmonary circulation pressures.     

Removal of pleural liquid and protein by lymphatics in awake sheep

The contribution of the parietal pleural lymphatics to pleural liquid and protein removal is unclear. We asked two questions. What is the rate of removal of sterile, artificial hydrothoraxes in awake sheep? What percentage is removed through parietal pleural lymphatics? Three days after the placement of a rib capsule in 18 sheep, we instilled a 10 ml/kg 1.0 g/dl autologous protein solution with labeled albumin and erythrocytes through the capsule into the pleural space. Erythrocytes were used as a marker for lymphatic flow. We measured terminal pleural liquid volume and radioactivity at periods from 2 to 48 h. In three sheep, we obtained a third volume measurement at 6 h by the volume of dilution technique. We found that hydrothorax removal could be described by a linear function with a constant rate: 0.28 +/- 0.01 ml.kg-1.h-1 (mean +/- SE) for the grouped data, and 0.20, 0.28, and 0.31 ml.kg-1.h-1 for the individual sheep. At 24 h, erythrocyte clearance was 89 +/- 16% (mean +/- SD) that of liquid and albumin clearance. We conclude that in awake sheep with large hydrothoraxes, pleural liquid and protein are removed at a rate of 0.28 +/- 0.01 ml.kg-1.h-1 (mean +/- SE) and lymphatics are responsible for at least 89% of this removal.     

Lung fluid balance during acute renal failure in sheep

To determine whether uremia changes lung vascular permeability, we measured the flow of lymph and proteins from the lungs of acutely uremic sheep. Acute renal failure was induced by either bilateral nephrectomy or by reinfusing urine. Both models of renal failure increased the plasma creatinine from 0.8 +/- 0.3 to 11 +/- 1 mg/dl in 3 days but caused no significant change in the flow of lymph from the lungs. To determine whether uremia increased the protein clearance response to elevated pulmonary microvascular pressures, we inflated a balloon in the left atrium for 2 h before and 3 days after inducing acute renal failure. In seven sheep, before removing the kidneys, the 20 cmH2O elevation of left atrial pressure increased the protein clearance 3.9 +/- 3.0 ml/h (from 9.5 +/- 4.9 to 13.4 +/- 5.4 ml/h). Three days after the bilateral nephrectomy the same increase in left atrial pressure increased the protein clearance 6.4 +/- 3.6 ml/h (from 6.1 +/- 2.1 to 12.5 +/- 5.2 ml/h), which was a significantly larger increase than that measured before the nephrectomy (P less than 0.05). Sham nephrectomy in seven sheep caused the protein clearance response to the elevated left atrial pressure to fall from 4.7 +/- 1.9 ml/h before the sham nephrectomy to 2.6 +/- 1.4 ml/h 3 days later (P less than 0.05). Uremia due to reinfusion of urine in five sheep did not affect the protein clearance response to elevations in left atrial pressure. Neither model of acute uremia increased the postmortem extravascular lung water volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isoproterenol improves ability of lung to clear edema in rats exposed to hyperoxia.

Exposure of adult rats to 100% O(2) results in lung injury and decreases active sodium transport and lung edema clearance. It has been reported that beta-adrenergic agonists increase lung edema clearance in normal rat lungs by upregulating alveolar epithelial Na(+)-K(+)-ATPase function. This study was designed to examine whether isoproterenol (Iso) affects lung edema clearance in rats exposed to 100% O(2) for 64 h. Active Na(+) transport and lung edema clearance decreased by approximately 44% in rats exposed to acute hyperoxia. Iso (10(-6) M) increased the ability of the lung to clear edema in room-air-breathing rats (from 0.50 +/- 0.02 to 0.99 +/- 0. 05 ml/h) and in rats exposed to 100% O(2) (from 0.28 +/- 0.03 to 0. 86 +/- 0.09 ml/h; P < 0.001). Disruption of intracellular microtubular transport of ion-transporting proteins by colchicine (0. 25 mg/100 g body wt) inhibited the stimulatory effects of Iso in hyperoxia-injured rat lungs, whereas the isomer beta-lumicolchicine, which does not affect microtubular transport, did not inhibit active Na(+) transport stimulated by Iso. Accordingly, Iso restored the lung's ability to clear edema after hyperoxic lung injury, probably by stimulation of the recruitment of ion-transporting proteins (Na(+)-K(+)-ATPase) from intracellular pools to the plasma membrane in rat alveolar epithelium.     

Effect of cAMP on ciliary function in rabbit tracheal epithelial cells

To study the effect of adenosine 3',5'-cyclic monophosphate (cAMP) on respiratory ciliary activity, we measured ciliary beat frequency (CBF) of rabbit tracheal epithelium by a photoelectric method in response to cAMP analogues and agents that can increase endogenous cAMP production. Addition of 8-bromo-cAMP dose dependently enhanced CBF, with the maximal increase and the concentration necessary to produce a half-maximal response (KD) being 31.0 +/- 3.4% (SE) (P less than 0.001) and 3.2 +/- 1.5 x 10(-7) M, respectively. Other structurally dissimilar cAMP analogues dibutyryl cAMP and chlorophenylthio-cAMP likewise caused increases in CBF. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the adenylate cyclase stimulator forskolin also augmented CBF in a dose-dependent fashion and were accompanied by the increases in intracellular concentrations of cAMP. Ciliary discoordination was not observed in any of the experiments. These results suggest that cAMP may accelerate mucociliary clearance through the activation of ciliary motility and that intracellular cAMP levels appear to be an important determinant for the lung mucociliary transport functions.     

Endothelial injury and pulmonary congestion characterize neurogenic pulmonary edema in rabbits

The objectives of the present study were to determine whether an intracisternal injection of fibrinogen-sodium citrate, a model of neurogenic pulmonary edema (NPE), produces protein-rich or protein-poor pulmonary edema, and to determine whether the edema is associated with pulmonary vascular hypertension and pulmonary congestion. Fibrinogen (6-10 mg/ml) dissolved in 0.055 M sodium citrate was injected into the cisterna magna of six New Zealand White rabbits. Six additional rabbits were injected with saline to control for the effects of intracranial hypertension and pulmonary vascular hypertension. The fibrinogen-sodium citrate solution or sodium citrate alone, as opposed to saline, produced systemic and pulmonary vascular hypertension, pulmonary edema, hypoxemia, hypercapnia, and acidosis. The lungs from fibrinogen-injected rabbits were edematous, congested, and liverlike in appearance. Tracheal froth that was blood tinged and protein rich was present in five of the six rabbits. Microscopic examination of lung biopsies revealed erythrocytes and plasma in the alveoli and focal injury to the pulmonary microvascular endothelium. Fibrinogen-sodium citrate increased (P less than 0.05) the extravascular lung water (EVLW) (10.3 +/- 2.0 vs. 5.5 +/- 0.6 g, means +/- SE), lung blood weight (9.7 +/- 1.3 vs. 3.8 +/- 0.6 g), total dry lung weight (3.2 +/- 0.4 vs. 2.0 +/- 0.1 g), and the EVLW-to-blood-free dry lung weight ratio (7.0 +/- 0.8 vs. 4.0 +/- 0.3 g) from saline-control values. There was no difference in the blood-fre dry lung weight (1.4 +/- 0.1 vs. 1.3 +/- 0.1 g) between the two groups. These findings demonstrate that pulmonary congestion, pulmonary vascular hypertension, and focal endothelial injury contribute to the development of NPE.