Alveolar hyperoxic injury in rabbits receiving exogenous surfactant

We have previously demonstrated that instillation of a calf lung surfactant extract (CLSE) in rabbits after exposure to 100% O2 for 64 h mitigates the progression of lung pathology after return to room air (J. Appl. Physiol. 62: 756-761, 1987). In the present study, we investigated whether we could prevent or reduce the onset and development of hyperoxic lung injury by sequential instillations of CLSE during the hyperoxic exposure. Rabbits were exposed to 100% O2. CLSE (125 mg, approximately 170 mumol of phospholipid) was suspended in 10 ml of sterile saline and instilled intratracheally into their lungs, starting at 24 h in O2, a time at which no physiological or biochemical injury was detected, and at 24-h intervals thereafter. Control rabbits breathed 100% O2 and received either equal volumes of saline or no instillations at all. CLSE-instilled rabbits had higher arterial PO2 (Pao2) values throughout the exposure period and survived longer when compared with saline controls [120 +/- 4 vs. 102 +/- 4 (SE) h; n greater than or equal to 10; P less than 0.05]. At 72 h in O2, CLSE-instilled rabbits had significantly higher lavageable alveolar phospholipid levels (12.5 +/- 1.5 vs. 5 +/- 1 mumol/kg) and total lung capacities (41 +/- 2 vs. 25 +/- 3.5 ml/kg) and lower levels of alveolar protein (24 +/- 3 vs. 52 +/- 8 mg/kg), minimum surface tension (2 +/- 1 vs. 26.1 dyn/cm), and lung wet-to-dry weights (5.9 +/- 0.2 vs. 6.5 +/- 0.3). After 72 h in O2, lungs from both CLSE- and saline-instilled rabbits showed evidence of diffuse hyperoxic injury. However, atelectasis was less prominent in the former. We concluded that instillation of CLSE limits the onset and development of hyperoxic lung injury to the alveolar epithelium of rabbits.     

Mitigation of pulmonary hyperoxic injury by administration of exogenous surfactant

We studied the effects of surfactant supplementation on the progression of lung injury in rabbits exposed to 100% O2 for 64 h and returned to room air for 24 h. At this time, rabbits not treated with surfactant exhibit a severe lung injury with hypoxemia, increased alveolar premeability to solute, decreased total lung capacity (TLC) and lung edema. For surfactant treatment, 125 mg of calf lung surfactant extract (CLSE), suspended in 6-8 ml of normal saline, were instilled intratracheally at 0 and 12 h posthyperoxic exposure. At 24 h postexposure, these CLSE-treated rabbits compared with saline controls had significantly higher amounts of lung phospolipids (34 +/- 4 vs. 4.5 +/- 0.6 mumol/kg body wt) and increased TLC (42 +/- 2 vs. 27 +/- 1 ml/kg), with significantly lower amounts of alveolar protein (36 +/- 3 vs. 56 +/- 3 mg/kg) and decreased lung wet weight-to-dry weight ratios (5.6 +/- 0.1 vs. 6.3 +/- 0.3). Surfactant supplementation also decreased the degree of lung atelectasis as reflected by the increase in arterial O2 partial pressure (PaO2) after breathing 100% O2 for 20 min (PaO2 = 460 +/- 31 vs. 197 +/- 52 Torr). These findings indicate that instillation of exogenous surfactant mitigates the progression of hyperoxic lung injury in rabbits.     

Surfactant replacement attenuates the increase in alveolar permeability in hyperoxia

Rabbits exposed to hyperoxia develop surfactant deficiency, abnormal lung mechanics, and increased permeability to solute. We investigated whether replenishment of depleted alveolar surfactant by the intratracheal instillation of calf lung surfactant extract (CLSE) would mitigate the increase in alveolar permeability to solute. Twenty-eight rabbits were exposed to 100% O2 for 72 h and received intratracheal instillations of 125 mg CLSE (approximately 170 mumol dipalmitoyl phosphatidylcholine) at 24 and 48 h. The interlobar and intralobar distribution of CLSE was quantified by adding [14C]dipalmitoyl phosphatidylcholine liposes into the instillate and measuring the levels of activity in lung tissue. CLSE was nonuniformly distributed in the different lung lobes, the right lower lobe receiving more CLSE than the rest. Alveolar epithelial permeability to solute was assessed by instilling 10 ml isotonic saline, which contained a trace amount of [57Co]cyanocobalamin, in the right lower lobe and measuring the disappearance of the tracer from the alveolar saline and its appearance in the arterial blood during a 1-h period. CLSE treatment was associated with significantly increased 72-h survival in hyperoxia compared with saline-treated controls (number of survivors: 16/17 vs. 5/11, P less than 0.01). CLSE treatment significantly reduced the rate constant for the movement of cyanocobalamin out of the alveolar space (24 +/- 5 vs. 42 +/- 6 min-1 x 10(-3), P less than 0.01) and tracer appearance in the blood at the end of the study (7 +/- 1 vs. 34 +/- 13%, P less than 0.01) when compared with values in saline controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory distress and surfactant inhibition following vagotomy in rabbits

We used the model of bilateral cervical vagotomy of adult rabbits to cause respiratory failure characterized by pulmonary edema, decreased lung compliance, and atelectasis. We documented an 18-fold increase in radiolabeled albumin leak from the vascular space into alveolar washes of vagotomy vs. sham-operated rabbits (P less than 0.01). Despite a twofold increase in percent of prelabeled saturated phosphatidylcholine secreted (P less than 0.01), the alveolar wash saturated phosphatidylcholine pool sizes were not different. The minimum surface tensions were 19.6 +/- 2.5 vs. 9.4 +/- 2.2 dyn/cm for alveolar washes from vagotomy and control rabbits, respectively (P less than 0.01). The soluble proteins from alveolar washes inhibited the surface tension lowering properties of natural surfactant, whereas those from the control rabbits did not (P less than 0.01). When vagotomy rabbits in respiratory failure were treated with 50 mg natural surfactant lipid per kilogram arterial blood gas values and compliances improved relative to control rabbits. Vagotomy results in alveolar pulmonary edema, and surfactant dysfunction despite normal surfactant pool sizes and respiratory failure. A surfactant treatment can improve the respiratory failure.     

Alveolar epithelial changes in rabbits after a 21-day exposure to 60% O2

This study characterizes the biochemical and physiological effects of prolonged exposure of rabbits to sublethal (60%) O2 concentrations. After 3 wk in 60% O2, rabbits had arterial PO2 values of 69 +/- 2 vs. 79 +/- 3 Torr for control animals (means +/- SE; P less than 0.05) and a small but significant rise in pulmonary wet weight-to-dry weight ratios (5.6 +/- 0.3 vs. 4.1 +/- 0.3; P less than 0.05). Alveolar permeability to solute, lung compliance, total lung capacity, and alveolar protein levels were unchanged from control, but the amount of lavagable alveolar phospholipid was 90% higher in the O2-exposed rabbits. The lipid biosynthetic ability of isolated alveolar type II pneumocytes, measured by radiolabeled precursor [3H]choline incorporation, indicated that type II cells isolated from hyperoxic animals synthesized phosphatidylcholine at a rate 110% higher than those from control animals. Laser flow cytometric analyses of isolated type II cells showed a significant increase in type II cell diameter, based on time-of-flight measurements, and an average 60% increase in lipid content per cell, based on phosphine-3R fluorescence intensity. These findings indicate that exposure to 60% O2 for 21 days results in a decrease in arterial PO2 and induces several important biochemical and morphological changes in alveolar type II pneumocytes.     

Pulmonary artery occlusion is sufficient to increase pulmonary vascular permeability in rabbits.

Unilateral pulmonary artery obstruction (PAO) for 24-48 h, followed by reperfusion, results in pulmonary edema and lung inflammation. We hypothesized that lung injury actually occurred during the period of PAO but, because of low microvascular pressures during the period of occlusion, was not detected until perfusion was reestablished. To test this hypothesis, we studied 14 rabbits divided into three groups: group I rabbits underwent sham occlusion of the left pulmonary artery for 24 h; group II rabbits underwent PAO but were not reperfused; and group III rabbits were subjected to PAO and then reperfused for 4 h. The fluid filtration coefficient measured during a zone 3 no-flow hydrostatic stress (pulmonary arterial pressure = pulmonary venous pressure, both greater than alveolar pressure) in group I lungs was less than that of lungs in either group II or III [0.52 +/- 0.02 (SE) ml.min-1.cmH2O.100 g wet wt-1 vs. 0.94 +/- 0.11 and 0.86 +/- 0.13 for groups II and III, respectively, P less than 0.05]. The wet-to-dry weight ratio of the left lung measured after the zone 3 stress was applied for 20 min was 6.90 +/- 0.09 in group I rabbits and 9.21 +/- 0.75 and 11.75 +/- 0.44 in groups II and III, respectively (P less than 0.05). Radiolabeled microspheres demonstrated that flow to the left lung was diminished after the period of PAO (38 +/- 4, 9 +/- 5, and 2 +/- 1% of cardiac output in groups I, II, and III, respectively; P less than 0.05 for group I vs. groups II and III).(ABSTRACT TRUNCATED AT 250 WORDS)     

Type II pneumocyte changes during hyperoxic lung injury and recovery

Adult rabbits exposed to 100% O2 for 64 h and then returned to room air for up to 200 h, develop a lung injury characterized by decreased levels of alveolar surfactant followed by a rebound recovery. In the present study we isolated alveolar type II cells from rabbits at various times during hyperoxic exposure and recovery and measured rates of phosphatidylcholine (PC) synthesis, cellular lipid content, and the specific activity of glycerol 3-phosphate (G-3-P) acyltransferase, an enzyme that catalyzes one of the early reactions in phosphoglyceride biosynthesis. These biochemical parameters were compared with measurements of cell size and cell cycle phase by laser flow cytometry. Results showed that alterations in alveolar phospholipid levels in vivo correlated consistently with cellular lipid metabolic changes measured in isolated type II pneumocytes. In particular, alveolar pneumocytes isolated from lungs of rabbits exposed to 100% O2 for 64 h exhibited a 60% decrease in PC synthesis, cell lipid content, and G-3-P acyltransferase activity. All variables then followed a pattern of recovery to normal and ultimately supranormal levels beginning at approximately 3 days postexposure, at which point there was also a measured increase in the number of type II cells in S phase. These findings suggest that O2-induced changes in type II cell surfactant biosynthesis may account, at least in part, for observed changes in lung phospholipid levels in vivo.     

Effects of ventilation on the surfactant system in sepsis-induced lung injury.

The present study examined the effects of mechanical ventilation, with or without positive end-expiratory pressure (PEEP), on the alveolar surfactant system in an animal model of sepsis-induced lung injury. Septic animals ventilated without PEEP had a significant deterioration in oxygenation compared with preventilated values (arterial PO(2)/inspired O(2) fraction 316 +/- 16 vs. 151 +/- 14 Torr; P < 0.05). This was associated with a significantly lower percentage of the functional large aggregates (59 +/- 3 vs. 72 +/- 4%) along with a significantly reduced function (minimum surface tension 17.7 +/- 1.8 vs. 11.8 +/- 3.8 mN/m) compared with nonventilated septic animals (P < 0.05). Sham animals similarly ventilated without PEEP maintained oxygenation, percent large aggregates and surfactant function. With the addition of PEEP, the deterioration in oxygenation was not observed in the septic animals and was associated with no alterations in the surfactant system. We conclude that animals with sepsis-induced lung injury are more susceptible to the harmful effects of mechanical ventilation, specifically lung collapse and reopening, and that alterations in alveolar surfactant may contribute to the development of lung dysfunction.     

Metabolism of testosterone to 17 beta-hydroxy-5 alpha-androstane-3-one and 5 alpha-androstane-3 alpha, 17 beta-diol in alveolar macrophages from rat lung--II. Effects of intratracheal instillation of 3.4 mumol K2Cr2O7

Activity of the steroid 5 alpha-reductase in pulmonary alveolar macrophages from adult male rats has been investigated in vitro. Intratracheal instillation of 3.4 mumol K2Cr2O7 lowered the enzyme activity within 6 h, and the reduction was significant on the subsequent 2, 4 and 7 days. The activity of this enzyme was significantly decreased only 6 and 24 h after instillation when measured in the 800 g supernatant fraction of whole lung. Instillation of 3.4 mumol K2Cr2O7 increased serum levels of corticosterone. Serum levels of triiodothyronine and thyroxine decreased except for a transient increase 3 h after the K2Cr2O7 instillation. Subcutaneous administration of 200 micrograms dexamethasone/100 g b.wt, 200 micrograms/100 g b.wt of testosterone, 17 beta-hydroxy-5 alpha-androstane-3-one (5 alpha-DHT), dehydroepiandrosterone or corticosterone had no effect on the 5 alpha-reductase activity of the pulmonary alveolar macrophages within 12 h. The combined treatment with dexamethasone s.c. and intratracheal instillation of 3.4 mumol K2Cr2O7 reduced the steroid 5 alpha-reductase activity in the pulmonary alveolar macrophages to about 25% of controls. Measurement of the steroid 5 alpha-reductase activity in pulmonary alveolar macrophages as an index of lung damage when exposed to toxic material is discussed.     

Phosphatidylglycerol-deficient lung surfactant has normal properties

We have investigated the effects of substituting phosphatidylinositol (PI) for phosphatidylglycerol (PG) on the functional properties of rabbit lung surfactant. We gave oral 10% glucose solution for 3 days to 11 rabbits and 10% inositol to 12 others. Lung lavage surfactant phospholipids were normal in both groups, except that PG was low and PI was high in the inositol group. Fatty acyl group distributions did not differ, except for a slight decrease of oleic acid in the inositol group. Electron microscopic examination showed normal surfactant structure in both. The time course of surfactant adsorption to an air-water interface was similar in both groups. Minimum surface tension after film compression was 4.0 +/- 0.8 mN . m-1 in the glucose group and 2.9 +/- 1.3 mN . m-1 in the inositol group (mean +/- SE). Surface potential-surface pressure isotherms were identical to within 12 mV. Arterial blood gases breathing air and 100% O2 were the same in both groups, as were pressure-volume curves of excised lungs, with both air and saline filling. The results suggest that, if acidic phospholipids are necessary for maintaining normal surfactant structure and surface properties, normal pressure-volume relationships, and normal gas exchange, then PI may substitute for PG.     

Pulmonary intravascular macrophages and hemodynamic effects of liposomes in sheep

We studied the effects of liposomes on the pulmonary circulation of sheep and found a close correlation between liposome retention in the lung and the intravascular macrophages. A test dose of liposomes (5.5 mumol of total lipids) injected intravenously transiently increased pulmonary arterial pressure from 24 +/- 2 to 55 +/- 16 (SD) cmH2O. The pulmonary arterial pressure responses were dose dependent and reproducible. The rise in pulmonary arterial pressure was blocked completely by indomethacin and 75% by a thromboxane synthase inhibitor. Systemic arterial thromboxane B2 concentration increased from a base-line level of less than 50 pg/ml to 250 +/- 130 pg/ml at the peak of the pressor response. Larger doses of liposomes (220 mumol of total lipids) infused intravenously over 1 h increased pulmonary arterial pressure maximally within the first 15 min. Lymph flow increased and lymph protein concentration decreased, suggesting venoconstriction. Over half (62.4 +/- 15.7%) of 111In-labeled liposomes remained in the lung after 2 h. Fluorescence and transmission electron microscopy showed that greater than 90% of the liposomes were associated with mononuclear cells in the lumen of the alveolar wall microvessels. We conclude that liposomes affect pulmonary arterial pressure transiently by a mechanism involving the arachidonate cascade, principally thromboxane. Our observations suggest that a population of pulmonary intravascular macrophages is likely to be the source of the thromboxane and the pulmonary hemodynamic and lymph dynamic changes that occur in a dose-dependent fashion, although interactions between liposomes, leukocytes, or endothelial cells, in addition to the macrophages, have not been completely ruled out. We believe this is the first demonstration that pulmonary intravascular macrophages may be the source of the arachidonate metabolites rather than endothelial cells, neutrophils, or perivascular interstitial cells.     

Effects of method of preservation on functions of livers from fed and fasted rabbits

Livers from fed, fasted (48 h) and glucose-fed rabbits were preserved for 24 and 48 h by either simple cold storage (CS) or continuous machine perfusion (MP) with the University of Wisconsin preservation solutions. After preservation liver functions were measured by isolated perfusion of the liver (at 37 degrees C) for 2 h. Fasting caused an 85% reduction in the concentration of glycogen in the liver but no change in ATP or glutathione. Glucose feeding suppressed the loss of glycogen (39% loss). After 24 h preservation by CS livers from fed or fasted animals were similar including bile production (6.2 +/- 0.5 and 5.6 +/- 0.4 ml/2 h, 100 g, respectively), hepatocellular injury (LDH release = 965 +/- 100 and 1049 +/- 284 U/liter), and concentrations of ATP (1.17 +/- 0.15 and 1.18 +/- 0.04 mumol/g, glutathione (1.94 +/- 0.51 and 2.35 +/- 0.26 mumol/g, respectively), and K:Na ratio (6.7 +/- 1.0 and 7.7 +/- 0.5, respectively). After 48 h CS livers from fed animals were superior to livers from fasted animals including significantly more bile production (5.0 +/- 0.9 vs 2.0 +/- 0.3 ml/2 h, 100 g), less LDH release (1123 +/- 98 vs 3701 +/- 562 U/liter), higher concentration of ATP (0.50 +/- 0.16 vs 0.33 +/- 0.07 mumol/g) and glutathione (0.93 +/- 0.14 vs 0.30 +/- 0.13 mumol/g), and a larger K:Na ratio (7.4 vs 1.5). Livers from fed animals were also better preserved than livers from fasted animals when the method was machine perfusion. The decrease in liver functions in livers from fasted animals preserved for 48 h by CS or MP was prevented by feeding glucose. Glucose feeding increased bile formation after 48 h CS preservation from 2.0 +/- 0.3 (fasted) to 6.9 +/- 1.2 ml/2 h, 100 g; LDH release was reduced from 3701 +/- 562 (fasted) to 1450 +/- 154 U/liter; ATP was increased from 0.33 +/- 0.07 (fasted) to 1.63 +/- 0.18 mumol/g; glutathione was increased from 0.30 +/- 0.01 (fasted) to 2.17 +/- 0.30 mumol g; and K:Na ratio was increased from 1.5 +/- 0.9 to 5.3 +/- 1.0. This study shows that the nutritional status of the donor can affect the quality of liver preservation. The improvement in preservation by feeding rabbits only glucose suggests that glycogen is an important metabolite for successful liver preservation. Glycogen may be a source for ATP synthesis during the early period of reperfusion of preserved livers.     

Acute and chronic hypoxic pulmonary hypertension in guinea pigs

To determine whether the strength of acute hypoxic vasoconstriction predicts the magnitude of chronic hypoxic pulmonary hypertension, we performed serial studies on guinea pigs. Unanesthetized, chronically catheterized guinea pigs increased mean pulmonary arterial pressure (PAP) from 11 +/- 0.5 to 13 +/- 0.7 Torr in acute hypoxia (10% O2 for 65 min). The response was maximal at 5 min, remained stable for 1 h, and was reversible on return to room air. Cardiac index did not change with acute hypoxia or recovery. Guinea pigs exposed to chronic hypoxia increased PAP, measured in room air 1 h after removal from the hypoxic chamber, to 18 +/- 1 Torr by 5 days with little further increase in PAP to 20 +/- 1 Torr after 21 days. Cardiac index fell from 273 +/- 12 to 206 +/- 7 ml.kg-1.min-1 (P less than 0.05) after 21 days of hypoxia. Medial thickness of pulmonary arteries adjacent to terminal bronchioles and alveolar ducts increased significantly by 10 days. The magnitude of the pulmonary vasoconstriction to acute hypoxia persisted and was unabated during the development and apparent stabilization of chronic hypoxic pulmonary hypertension, suggesting that if vasoconstriction is the stimulus for remodeling, then the importance of the stimulus lessens with duration of hypoxia. In individual animals followed serially, we found no correlation between the magnitude of the acute vasoconstrictor response before chronic hypoxia and the severity of chronic pulmonary hypertension that subsequently developed either because the initial response was small and variable or because vasoconstriction may not be the sole stimulus for vascular remodeling in the guinea pig.     

Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs.

The purpose of this study was to determine whether pulmonary venous pressure increases during alveolar hypoxia in lungs of newborn pigs. We isolated and perfused with blood the lungs from seven newborn pigs, 6-7 days old. We maintained blood flow constant at 50 ml.min-1.kg-1 and continuously monitored pulmonary arterial and left atrial pressures. Using the micropuncture technique, we measured pressures in 10 to 60-microns-diam venules during inflation with normoxic (21% O2-69-74% N2-5-10% CO2) and hypoxic (90-95% N2-5-10% CO2) gas mixtures. PO2 was 142 +/- 21 Torr during normoxia and 20 +/- 4 Torr during hypoxia. During micropuncture we inflated the lungs to a constant airway pressure of 5 cmH2O and kept left atrial pressure greater than airway pressure (zone 3). During hypoxia, pulmonary arterial pressure increased by 69 +/- 24% and pressure in small venules increased by 40 +/- 23%. These results are similar to those obtained with newborn lambs and ferrets but differ from results with newborn rabbits. The site of hypoxic vasoconstriction in newborn lungs is species dependent.     

N omega-nitro-L-arginine influences cerebral metabolism in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide (NO). An inhibitor of NO formation, N omega-nitro-L-arginine (LNA, 100 micrograms/kg i.v.), was given to conscious sheep (n = 6) during normoxia and again in hypocapnic hypoxia (arterial PO2 approximately 38 Torr). Blood samples were obtained from the aorta and sagittal sinus, and cerebral blood flow (CBF) was measured with 15-microns radiolabeled microspheres. During normoxia, LNA elevated (P < 0.05) mean arterial pressure from 82 +/- 3 to 88 +/- 2 (SE) mmHg and cerebral perfusion pressure (CPP) from 72 +/- 3 to 79 +/- 3 mmHg, CBF was unchanged, and cerebral lactate release (CLR) rose temporarily from 0.0 +/- 1.9 to 13.3 +/- 8.7 mumol.min-1 x 100 g-1 (P < 0.05). The glucose-O2 index declined (P < 0.05) from 1.67 +/- 0.16 to 1.03 +/- 0.4 mumol.min-1 x 100 g-1. Hypoxia increased CBF from 59.9 +/- 5.4 to 122.5 +/- 17.5 ml.min-1 x 100 g-1 and the glucose-O2 index from 1.75 +/- 0.43 to 2.49 +/- 0.52 mumol.min-1 x 100 g-1 and decreased brain CO2 output, brain respiratory quotient, and CPP (all P < 0.05), while cerebral O2 uptake, CLR, and CPP were unchanged. LNA given during hypoxia decreased CBF to 77.7 +/- 11.8 ml.min-1 x 100 g-1 and cerebral O2 uptake from 154 +/- 22 to 105.2 +/- 12.4 mumol.min-1 x 100 g-1 and further elevated mean arterial pressure to 98 +/- 2 mmHg (all P < 0.05), CLR was unchanged, and, surprisingly, brain CO2 output and respiratory quotient were reduced dramatically to negative values (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of pulmonary oxygen toxicity by bleomycin treatment

The purpose of this study was to determine whether pretreatment of rabbits with bleomycin would modify their response to 100% O2 and, if so, to identify the mechanism of this action. A single intratracheal injection of bleomycin (5 U/kg) resulted in a transient decrease of the arterial Po2, its mean value (+/- SE) 7 days postinjection being 59 +/- 3 Torr. All animals were either killed or exposed to 100% O2 35 days postinjection. At this time, arterial Po2 had returned to its control level. On the other hand, lung hydroxyproline content had doubled and static compliance and the total lung capacity had decreased by 22 and 31%, respectively, indicating the existence of significant lung fibrosis. Furthermore, activities of catalase and superoxide dismutase in lung homogenates were higher than control and were further augmented by exposure to 100% O2 for 64 h. These biochemical changes may account, at least in part, for the mitigation of the toxic effects of hyperoxia, as shown by the delayed appearance of arterial hypoxemia, and the 50% increase in survival time when bleomycin injected rabbits were exposed to 100% O2 35 days postinjection.     

Regional alveolar hypoxia does not affect air embolism-induced pulmonary edema

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema resulting from venous air embolization. Anesthetized dogs had the left upper lobe removed and a double-lumen tube placed so that right lung and left lower lobe (LLL) could be ventilated independently. Air was infused into the femoral vein for 1 h during bilateral ventilation at an inspiratory O2 fraction (FIO2) of 1.0. After cessation of air infusion the LLL was then ventilated with a hypoxic gas mixture (FIO2 = 0.05) in six animals and an FIO2 of 1.0 in six other animals. Lung hydroxyproline content was measured as an index of lung dry weight. LLL bloodless lobar wet weight-to-hydroxyproline ratio was 0.33 +/- 0.06 mg/micrograms in the animals exposed to LLL hypoxia and 0.37 +/- 0.03 mg/micrograms (NS) in the animals that had a LLL FIO2 of 1. Both values were significantly higher than our laboratory normal values of 0.19 +/- 0.01 mg/micrograms. We subsequently found in four more dogs exposed to global alveolar hypoxia before and after air embolism that the air injury itself significantly depressed the hypoxic vasoconstrictor response. We conclude that regional alveolar hypoxia has no effect on pulmonary edema formation due to air embolism. The most likely reason for these findings is that the air embolism injury itself interfered with hypoxic pulmonary vasoconstriction.     

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs.

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary NO and CO2 uptake during pressure-induced lung expansion in rabbits

In artificially ventilated animals we investigated the dependence of the pulmonary diffusing capacities of nitric oxide (NO) and doubly 18O-labeled carbon dioxide (DLNO, DLC18O2) on lung expansion with respect to ventilator-driven increases in intrapulmonary pressure. For this purpose we applied computerized single-breath experiments to 11 anesthetized paralyzed rabbits (weight 2.8-3.8 kg) at various alveolar volumes (45-72 ml) by studying the almost entire inspiratory limb of the respective pressure/volume curves (intrapulmonary pressure: 6-27 cmH2O). The animals were ventilated with room air, employing a computerized ventilatory servo-system that we designed to maintain mechanical ventilation and to execute the particular lung function tests automatically. Each single-breath maneuver was started from residual volume (13.5+/-2 ml, mean+/-SD) by inflating the rabbit lungs with 35-55 ml indicator gas mixture containing 0.05% NO in N2 or 0.9% C18O2 in N2. Alveolar partial pressures of NO and C18O2 were measured by respiratory mass spectrometry. Values of DLNO and DLC18O2 ranged between 1.55 and 2.49 ml/(mmHg min) and 11.7 and 16.6 ml/(mmHg min), respectively. Linear regression analyses yielded a significant increase in DLNO with simultaneous increase in alveolar volume (P<0.005) and intrapulmonary pressure (P<0.023) whereas DLC18O2 was not improved. Our results suggest that the ventilator-driven lung expansion impaired the C18O2 blood uptake conductance, finally compensating for the beneficial effect of the increase in alveolar volume on DLC18O2 values.