Nebulized vs. instilled exogenous surfactant in an adult lung injury model.

Three days after subcutaneous injection of N-nitroso-N-methylurethane (NNNMU) to induce lung injury, adult rabbits were mechanically ventilated and lung function was evaluated. Each animal then received either nebulized Survanta (Neb Surv), nebulized saline (Neb Saline), nebulized gas alone (Neb Gas), or tracheally instilled Survanta (Inst Surv). The ventilation efficiency index (VEI) value increased significantly compared with pretreatment values (P less than 0.01) over a 3-h treatment period for the Neb Surv animals, whereas VEI values for the other three groups decreased after treatment (P less than 0.05). Arterial PO2-to-fraction of inspired O2 ratios and dynamic compliance values significantly decreased after treatment for the Inst Surv group (P less than 0.05). Pressure-volume curves demonstrated a significantly greater volume at maximal pressure for the Neb Surv group compared with each of the other groups studied (P less than 0.01). The calculated quantity of surfactant recovered in lung tissue for the Neb Surv group was only 4.9 +/- 1.0 mg lipid/kg compared with 100 mg lipid/kg delivered to the Inst Surv group. Surfactant administered as an aerosol resulted in modest physiological improvements in this model of lung injury and was superior to the tracheal instillation technique.     

Corticosteroid potentiation of surfactant dose response in preterm rabbits

Fetal rabbits were treated with corticosteroids by maternal administration for 48 h before delivery at 27 days gestational age. Both corticosteroid-treated and control animals then received exogenous natural rabbit surfactant at birth at doses of 0-75 mg lipid/kg. After 10 min of ventilation at tidal volumes of 12-15 ml/kg, static pressure-volume measurements were made. At all surfactant doses there was a significantly higher maximal lung volume, higher dynamic compliance, and lower pressure requirement in the corticosteroid-treated than in the control rabbits (P less than 0.01). Control animals showed incremental improvements in dynamic compliances and maximal lung volumes up to a dose of 50 mg/kg, whereas corticosteroid treated animals improved to a maximum at the low dose of 15 mg/kg (P less than 0.01). However, surface tension as assessed by lung stability index improved with increasing surfactant dose but was not significantly different between corticosteroid-treated and control animals at a given dose. The results imply that maternal corticosteroid treatment potentiates surfactant replacement by a change in lung structure that is independent of surface tension effects.     

Corticosteroids and surfactant increase lung volumes and decrease rupture pressures of preterm rabbit lungs

We measured the effects of corticosteroids and surfactant individually and in combination on lung pressure-volume relationships, rupture pressures, and rupture volumes. Pregnant does were injected with betamethasone (0.1 mg/kg per day im) or vehicle on days 24 and 25 of gestation, and fetal rabbits were delivered on days 26 and 27. Natural surfactant (50 mg/kg body wt) was instilled intratracheally into half of the lungs after tracheotomy. After nine cycles of inflation with air to 40 cmH2O and deflation, air pressure-volume curves were measured. Then the lungs were filled with air to rupture, and rupture volume and pressure were recorded. Both corticosteroids and surfactant caused an increase in maximal lung volumes (P less than 0.01) and a decrease of lung rupture pressures (P less than 0.01) compared with controls. The effects of corticosteroids plus surfactant on lung volumes were the sum of each effect individually, but rupture pressures were the same as those for corticosteroids or surfactant alone. Surfactant, in addition, caused an increase in lung stability at deflation, an effect that was not evident in the corticosteroid-treated groups. Measurements of saturated phosphatidylcholine in alveolar washes and lung tissue indicated comparable values in the corticosteroid and control groups. We conclude that changes in static properties and rupture pressures presumably reflect changes in lung structure caused by corticosteroids that are independent of a corticosteroid effect on surfactant pool sizes.     

Soluble nitric oxide donor and surfactant improve oxygenation and pulmonary hypertension in porcine lung injury.

Acute lung injury (ALI) is associated with diminished surfactant activity and pulmonary hypertension. NONOates are soluble NO donors which release NO in solution. Intratracheal NONOates reduce pulmonary hypertension and improve oxygenation in ALI. We hypothesized that the pharmacologic properties of NO donors would be unaltered after surfactant admixture in vitro and that aerosolized NONOate activity would be enhanced by surfactant pretreatment in vivo. NO donors were added to saline or surfactant and analyzed for nitrite/nitrate production and aortic ring vasodilation. Surfactant did not alter nitrate/nitrite production or aortic ring vasodilation. A porcine model of ALI with pulmonary hypertension was produced using intravenous oleic acid. Animals were assigned to Surfactant-Saline, Surfactant-NONOate, Saline-Saline, or Saline-NONOate groups. Saline or surfactant was instilled into the trachea, followed by gas exchange, pulmonary function, and hemodynamic measurements. NONOate or saline was then aerosolized, and additional data were collected. Oxygenation was improved in the Surfactant-NONOate group, while pulmonary hypertension was selectively reduced in both NONOate groups. Aerosolized NONOate following surfactant pretreatment improves oxygenation and reduces pulmonary hypertension in ALI.     

Different ventilation strategies alter surfactant responses in preterm rabbits.

The effect of ventilation strategy on in vivo function of different surfactants was evaluated in preterm rabbits delivered at 27 days gestational age and ventilated with either 0 cmH2O positive end-expiratory pressure (PEEP) at tidal volumes of 10-11 ml/kg or 3 cmH2O PEEP at tidal volumes of 7-8 ml/kg after treatment with one of four different surfactants: sheep surfactant, the lipids of sheep surfactant stripped of protein (LH-20 lipid), Exosurf, and Survanta. The use of 3 cmH2O PEEP decreased pneumothoraces in all groups except for the sheep surfactant group where pneumothoraces increased (P < 0.01). Ventilatory pressures (peak pressures - PEEP) decreased more with the 3 cmH2O PEEP, low-tidal-volume ventilation strategy for Exosurf-, Survanta-, and sheep surfactant-treated rabbits (P < 0.05), whereas ventilation efficiency indexes (VEI) improved only for Survanta- and sheep surfactant-treated rabbits with 3 cmH2O PEEP (P < 0.01). Pressure-volume curves for sheep surfactant-treated rabbits were better than for all other treated groups (P < 0.01), although Exosurf and Survanta increased lung volumes above those in control rabbits (P < 0.05). The recovery of intravascular radiolabeled albumin in the lungs and alveolar washes was used as an indicator of pulmonary edema. Only Survanta and sheep surfactant decreased protein leaks in the absence of PEEP, whereas all treatments decreased labeled albumin recoveries when 3 cmH2O PEEP was used (P < 0.05). These experiments demonstrate that ventilation style will alter a number of measurements of surfactant function, and the effects differ for different surfactants.     

Large-volume ventilation results in bronchoconstriction of Basenji-Greyhound dogs

We compared the effects of large-volume ventilation on airway responses to aerosolized histamine in anesthetized mongrel dogs with its effects in Basenji-Greyhound crossbred (B-G) dogs. Before bronchoconstriction, large inflations resulted in only small changes of dynamic compliance (Cdyn) and pulmonary resistance (RL) in both groups of dogs. After the induction of a moderate degree of bronchoconstriction with aerosolized histamine, large inflations had a more substantial effect; Cdyn increased by 7.5 +/- 2.3% (mean +/- SE; P less than 0.05), and RL decreased by 32 +/- 3.4% (P less than 0.001) in the mongrel dogs. In the B-G group, Cdyn increased by only 0.2 +/- 1.8% (NS), and RL increased by 29.3 +/- 9.2% (P less than 0.05); these changes differed significantly (P less than 0.05) from those observed in the mongrel dogs. Large-volume ventilation following the administration of indomethacin (10 mg/kg iv) and histamine increased Cdyn by 11.4 +/- 1.8% (NS vs. without indomethacin) and decreased RL by 43.9 +/- 3.4% (P less than 0.05) in the mongrel group. In the B-G group large-volume ventilation increased Cdyn by 7.6 +/- 1.7% (P less than 0.01) and decreased RL by 15.7 +/- 8.1% (P less than 0.05). Thus indomethacin enhanced the bronchodilator effects of large-volume ventilation in mongrel dogs and reversed the bronchoconstrictor effect of this maneuver on RL in B-G dogs.     

Altered function of pulmonary surfactant in fatty acid lung injury

To determine whether acute fatty acid lung injury impairs pulmonary surfactant function, we studied anesthetized ventilated rabbits given oleic acid (55 mg/kg iv, n = 11) or an equivalent volume of saline (n = 8). Measurements of pulmonary mechanics indicated a decrease in dynamic compliance within 5 min of injury and a decrease in lung volume that was disproportionately large at low pressures, consistent with diminished surfactant activity in vivo. Bronchoalveolar lavage fluid obtained 1 h after injury had significantly increased erythrocytes and total leukocytes, largely polymorphonuclear cells. The phospholipid content and composition of the cell-free fraction had only minor changes from those of controls, but the protein content was increased 35-fold. Measurements of lavage surface activity in vitro showed an increase in average minimum surface tension from 1.3 +/- 0.4 (SE) dyn/cm in controls to 20.2 +/- 3.9 dyn/cm in injured animals. The alterations in static pressure-volume curves and decrease in lavage surface activity suggest a severe alteration of surfactant function in this form of lung injury that occurs despite the presence of normal amounts of surfactant phospholipids.     

Effect of artificial surfactant on pulmonary function in preterm and full-term lambs

We hypothesized that agents very different from surfactant may still support lung function. To test this hypothesis, we instilled FC-100, a fluorocarbon, and Tween 20, a detergent, which have higher minimum surface tensions and less hysteresis than surfactant, into 15 full-term and 14 preterm lambs. FC-100 and Tween 20 were as efficient as natural surfactant in improving gas exchange and compliance in preterm lambs with respiratory failure. Dynamic compliance correlated with the equilibrium surface tension of the alveolar wash in both full-term (P less than 0.02) and preterm (P less than 0.008) lambs. Functional residual capacity in full-term and preterm lambs was lower after treatment with the two test agents than with surfactant, findings consistent with qualitative histology. Oxygenation in full-term lambs correlated with mean lung volumes (P less than 0.003), suggesting that the hysteresis and/or low minimum surface tension of surfactant may improve mean lung volume, and hence oxygenation, by maintaining functional residual capacity. The effects of the test agents suggest that agents with biophysical properties different from surfactant may still aid lung expansion.     

Antenatal betamethasone dose effects in preterm rabbits studied at 27 days gestation

Pregnant rabbits received bethamethasone (0.05, 0.2, 0.4, or 0.5 mg.kg-1.day-1) or vehicle control for 2 days before delivery of fetuses at 27 days gestation to evaluate dose-related effects on surfactant pool sizes with and without ventilation, pressure-volume measurements, lung protein leaks, and precursor incorporation into lung saturated phosphatidylcholine (PC). Alveolar wash-saturated PC pool sizes in betamethasone-exposed fetuses were less than in controls (P less than 0.01). At higher doses, total lung saturated PC also decreased (P less than 0.01). Maximal lung volumes on pressure-volume loops were larger than controls only at the 0.4 mg.kg-1.day-1 dose (P less than 0.05). The larger maximal volumes, despite decreased saturated PC pools, indicated increased responsiveness of the steroid-treated lungs to the smaller saturated PC pool sizes. Vascular-to-alveolar iodinated albumin leak decreased with steroid treatment independently of dose (P less than 0.01). No consistent pattern of increased precursor incorporation into saturated PC by lung slices was seen. Our results indicate that, in preterm rabbits exposed to a range of maternal corticosteroid doses, the beneficial lung maturational effect of structural alterations with increased responses to endogenous saturated PC pools was maximal even at the lowest dose.     

Surfactant metabolism in surfactant-treated preterm ventilated lambs

Preterm lambs were delivered at 132 days gestational age, treated with 100 mg/kg radiolabeled natural sheep surfactant or Surfactant TA, and ventilated for times up to 24 h. Compared with an untreated group that developed respiratory failure by 5 h, both surfactant-treated groups had stable respiratory function to 24 h. Although only approximately 13% of the labeled surfactant phosphatidylcholine was recovered by alveolar wash at 24 h, there was no significant loss of the labeled phosphatidylcholine from the lungs. Labeled palmitic acid intravascularly injected at 1 h of age comparably labeled lung phosphatidylcholine in the three groups of lambs at 5 h; however, only approximately 0.5% of the labeled phosphatidylcholine was secreted to the air spaces of surfactant-treated lambs at 24 h. Labeled lysophosphatidylcholine given with the natural sheep surfactant was taken up by the lungs, converted to phosphatidylcholine with 30-40% efficiency, and resecreted to the air spaces, demonstrating recycling of a phospholipid. The large surfactant aggregates recovered from alveolar washes by centrifugation were surface active and contained approximately 76% of the air-space phosphatidylcholine in both surfactant-treated groups. Although clinical status was comparable, alveolar washes and surfactant subfractions from Surfactant TA-treated lambs had better surface properties than did sheep surfactant-treated lambs. These studies identified no detrimental effects of surfactant treatments on endogenous surfactant metabolism and indicated that the surfactants used for treatments were recycled by the preterm ventilated lamb lung.     

Effect of distortion on the mechanical properties of newborn piglet lung

During breathing the relatively high chest wall-to-lung compliance ratio of the newborn favors distortion of the respiratory system. In this study we have examined the effect of lung deformation, generated by a hydrostatic pleural surface pressure gradient, on the static (Cstat) and dynamic (Cdyn) compliance of the isolated newborn piglet lung. Seven lungs from piglets 2-7 days old have been studied in a saline-filled plethysmograph. Static pressure-volume (PV) curves were obtained by changing the volume a known amount and measuring the corresponding changes in transpulmonary pressure. Dynamic PV curves were obtained by ventilating the lung at a fixed pressure and at 20 cycles/min. These experiments were repeated in an air plethysmograph on the undeformed lung. Lung volume history was standardized prior to each maneuver by three inflations to 20-25 cmH2O. Lung collapse was avoided by applying an end-expiratory load equal to the transpulmonary pressure at functional residual capacity. Cstat was not significantly different between the deformed and undeformed lung (P greater than 0.05). Cdyn was less than Cstat in both cases (P less than 0.025) and was reduced further by deformation (P less than 0.05). We conclude that 1) peripheral airway obstruction or the viscoelastic properties of the piglet lung, or both, decrease Cdyn, and 2) deformation increases the external (PV) respiratory work by further decreasing Cdyn.     

PEEP is necessary for exogenous surfactant to reduce pulmonary edema in canine aspiration pneumonitis.

Alveolar edema inactivates surfactant, and surfactant depletion causes edema by reducing lung interstitial pressure (Pis). We reasoned that surfactant repletion might reduce edema by raising Pis after acute lung injury and that positive end-expiratory pressure (PEEP) might facilitate this effect. One hour after tracheal administration of hydrochloric acid in 18 anesthetized dogs with transmural pulmonary capillary wedge pressure of 8 Torr, the animals were randomized into three groups: in the SURF + PEEP group, 50 mg/kg of calf lung surfactant extract (CLSE) was instilled into each main stem bronchus with 8 cmH2O of PEEP; in the SAL + PEEP group, PEEP was followed by an equal volume of saline (SAL); in the SURF group, CLSE was given without PEEP. After 5 h, edema in excised lungs (wet-to-dry weight ratios) was significantly less in the SURF + PEEP group (9.1 +/- 1.0) than in the other groups (11.3 +/- 1.8 and 11.3 +/- 1.8, respectively). In the SURF + PEEP group, pulmonary venous admixture fell by 6%; this change was different from the 7% increase in the SAL + PEEP group and 40% increase in the SURF group (P less than 0.05). Airway secretions obtained in the SURF + PEEP group had normal minimum surface tensions of 4 +/- 2 mN/m, a value much lower than in SAL + PEEP and SURF groups (32 +/- 4 and 22 +/- 7 mN/m, respectively). We conclude that surfactant normalizes surface tension and decreases transcapillary hydrostatic forces in this lung injury model, thereby reducing edema formation and improving gas exchange. These benefits occur only if surfactant is given with PEEP, allowing surfactant access to the alveoli and/or minimizing its inhibition by edema proteins.     

Lung mechanics in papain-treated rabbits

To further investigate the effects of airway cartilage softening on static and dynamic lung mechanics, 11 rabbits were treated with 100 mg/kg iv papain, whereas 9 control animals received no pretreatment. Lung mechanics were studied 24 h after papain injection. There was no significant difference in lung volumes, lung pressure-volume curves, or chest wall compliance. Papain-treated rabbits showed increased lung resistance: 91 +/- 63 vs. 39 +/- 22 cmH2O X l-1 X s (mean +/- SD; P less than 0.05), decreased maximal expiratory flows at all lung volumes, and preserved density dependence of maximal expiratory flows. We conclude that increased airway wall compliance is probably the mechanism that limited maximal expiratory flow in this animal model. In addition the increased lung resistance suggests that airway cartilage plays a role in the regulation of airway caliber during quiet tidal breathing.     

硫化氢对大鼠内毒素性急性肺损伤肺泡表面活性物质的影响

目的：观察脂多糖（LPS）所致内毒素性急性肺损伤（ALI）大鼠肺泡表面活性物质（PS）的变化及硫化氢（H2S）对PS的影响,探讨H2S对肺脏的作用机制。方法：雄性SD大鼠共48只,随机分为6组（n=8）：空白对照组、LPS组、LPS＋NaHS低、中、高剂量组、LPS＋PPG组。空白对照组给予生理盐水,LPS组给予LPS,LPS＋NaHS低、中、高剂量组和LPS＋PPG组分别在给予LPS3h时腹腔注射低、中、高剂量氢硫化钠（NariS）或炔丙基甘氨酸（PPG）。各组均于给予生理盐水或LPS6h时电镜下观察肺泡Ⅱ型上皮细胞（AEC-Ⅱ）的形态改变,检测血浆中H2S含量、肺组织中胱硫醚-γ-裂解酶（CSE）活性、肺泡灌洗液（BALF）中总蛋白（1P）和总磷脂（TPL）含量、及肺组织中肺泡表面活性蛋白A、B、C（SP-A、B、C）mRNA表达的变化。结果：①与空白对照组比较,LPS组AEC-Ⅱ超微结构明显受损,血浆中H2S含量、肺组织中CSE活性、BALF中TPL的含量、及肺组织中SP-A、B、CmRNA表达均明显降低（P〈0．05,P〈0．01）,BALF中TP的含量明显增加（P〈0．01）;②与LPS组比较,LPS＋NaHS低、中、高剂量组,AEC-Ⅱ超微结构均有所恢复,血浆中H2S含量、肺组织中CSE海性、SP-AmRNA表达均明显升高（P〈0．05,P〈0．01）;LPS＋NaHS中、高剂量组BALF中吼含量明显增高,SP-BmRNA表达升高（P〈0．05）;LPS＋NaHS高剂量组BALF中,IP含量明显降低（P〈0．05）;LPS＋NaHS各剂量组SP-CznRNA表达无明显变化;③与LPS组比较,LPS＋PPG组AEC-Ⅱ超微结构仍损伤严重,血浆中H2S含量、肺组织中CSE活性、BALF中TPL的含量、及肺组织中SP-A、B、CmRNA表达均明显降低（P〈0．05）,BALF中TP的含量明显升高（P〈0．05）。结论：PS降低是内毒素性ALI的重要病理生理过程,H2S对LPS诱导的ALI有保护性作用,其机制可能与H2S对PS的调节有关。     

Surfactant treatments alter endogenous surfactant metabolism in rabbit lungs

The effect of exogenous surfactant on endogenous surfactant metabolism was evaluated using a single-lobe treatment strategy to compare effects of treated with untreated lung within the same rabbit. Natural rabbit surfactant, Survanta, or 0.45% NaCl was injected into the left main stem bronchus by use of a Swan-Ganz catheter. Radio-labeled palmitic acid was then given by intravascular injection at two times after surfactant treatment, and the ratios of label incorporation and secretion in the left lower lobe to label incorporation and secretion in the right lung were compared. The treatment procedure resulted in a reasonably uniform surfactant distribution and did not disrupt lobar pulmonary blood flow. Natural rabbit surfactant increased incorporation of palmitate into saturated phosphatidylcholine (Sat PC) approximately 2-fold (P less than 0.01), and secretion of labeled Sat PC increased approximately 2.5-fold in the surfactant-treated left lower lobe relative to the right lung (P less than 0.01). Although Survanta did not alter incorporation, it did increase secretion but not to the same extent as rabbit surfactant (P less than 0.01). Alteration of endogenous surfactant Sat PC metabolism in vivo by surfactant treatments was different from that which would have been predicted by previous in vitro studies.     

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.     

Biophysical inhibition of synthetic lung surfactants

The biophysical activity and inhibition of a series of synthetic surfactant mixtures was studied and correlated with physiological effectiveness in restoring pressure-volume (P-V) mechanics of excised lungs. Results showed that several simple mixtures of dipalmitoyl phosphatidylcholine (DPPC) with fatty acids or diacylglycerols could be formulated to give good adsorption facility and dynamic surface tension lowering to less than 1 mN/m in pulsating bubble measurements at 37 degrees C. However, although biophysical activity approached that of natural lung surfactant (LS) and a related surfactant extract (CLSE) under normal conditions, surface properties were sharply inhibited by relatively small amounts of the plasma protein albumin (2 mg/ml) with minimum surface tensions greater than 30 nM/m even at high surfactant concentrations (5-20 mg lipids/ml). This sensitivity to biophysical inhibition was markedly increased compared to LS and CLSE, and had direct consequences for physiological efficacy: in spite of initially high activity, synthetic surfactants did not exert beneficial effects on P-V mechanics when instilled into surfactant-deficient excised rat lungs. Endogenous protein material was shown to be present upon surfactant recovery by lavage, and bubble measurements confirmed surface activity well below pre-instillation levels. Moreover, full biophysical activity was restored when lavage fluid was extracted to separate the synthetic surfactants from endogenous inhibitors. These results show that it is important to define relative sensitivity to biophysical inhibition in the development of effective lung surfactant substitutes. In addition, the existence of inhibition effects can generate an apparent lack of correspondence between initial biophysical activity and ultimate physiological actions of exogenous surfactant mixtures.     

Collateral ventilation during high-frequency oscillation in dogs

Mechanics of collateral channels during high-frequency oscillatory ventilation (HFOV) were assessed in eight anesthetized dogs, using a modification of Hilpert's technique. Base-line functional residual capacity was measured with a body plethysmograph, with inspiratory efforts induced by phrenic nerve stimulation. The resistance (Rcoll) and time constant (Tcoll) of collateral channels at five lung volumes were measured during HFOV and positive end-expiratory pressure (PEEP). Rcoll and Tcoll were significantly higher during HFOV (P less than 0.001); the differences did not correlate with resting lung volumes. The calculated static compliance of the wedged segment was similar during HFOV and PEEP (P greater than 0.005). Mean pressures measured in small airways during HFOV corresponded to the midline between the inflation and deflation limbs of the static pressure-volume curves, indicating similar pressure-volume characteristics of the respiratory system during HFOV and static conditions. We conclude that HFOV increases resistance to gas flow through collateral channels but that this pathway may still be important in gas exchange.     

Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity

These experiments characterize the effects of hemoglobin and erythrocyte membrane lipids on the dynamic surface activity and adsorption facility of whole lung surfactant (LS) and a calf lung surfactant extract (CLSE) used clinically in surfactant replacement therapy for the neonatal respiratory distress syndrome (RDS). The results show that, at concentrations from 25 to 200 mg/ml, hemoglobin (Hb) increased the minimum dynamic surface tension of LS or CLSE mixtures (0.5 and 1.0 mumol/ml) from less than 1 to 25 dyn/cm on an oscillating bubble apparatus at 37 degrees C. Similarly, erythrocyte membrane lipids (0.5-3 mumol/ml) also prevented LS and CLSE suspensions (0.5-2.0 mumol/ml) from lowering surface tension below 19 dyn/cm under dynamic compression on the bubble. Surface pressure-time adsorption isotherms for LS suspensions (0.084 and 0.168 mumol phospholipid/ml) were also adversely affected by Hb (0.3-2.5 mg/ml), having a slower adsorption rate and magnitude. Significantly, these inhibitory effects of Hb and membrane lipids could be abolished if LS and CLSE concentrations were raised to high levels. In complementary physiological experiments, instillation of Hb, membrane lipids, or albumin into excised rat lungs was shown to cause a decrease in pressure-volume compliance. This decreased compliance was most prominent in lungs made partially surfactant deficient before inhibitor delivery and could be reversed by supplementation with active exogenous surfactant. Taken together, these data show that molecular components in hemorrhagic pulmonary edema can biophysically inactivate endogenous LS and adversely affect lung mechanics. Moreover, exogenous surfactant replacement can reverse this process even in the continued presence of inhibitor molecules and thus has potential utility in therapy for adult as well as neonatal RDS.     

Limb venous compliance in patients with idiopathic orthostatic intolerance and postural tachycardia.

Venous denervation and increased venous pooling may contribute to symptoms of orthostatic intolerance. We examined venous compliance in the calf and forearm in 11 orthostatic-intolerant patients and 15 age-matched controls over a range of pressures, during basal conditions and sympathetic excitation. Occlusion cuffs placed around the upper arm and thigh were inflated to 60 mmHg and deflated to 10 mmHg over 1 min. Limb volume was measured continuously with a mercury-in-Silastic strain gauge. Compliance was calculated as the numerical derivative of the pressure-volume curve. The pressure-volume relationship in the upper and lower extremities in the basal and sympathetically activated state was significantly lower in the orthostatic-intolerant patients (all P < 0.05). Sympathoexcitation lowered the pressure-volume relationship in the lower extremity in patients (P < 0.001) and controls (P < 0.01). Venous compliance was significantly less in patients in the lower extremity in the basal state over a range of pressures (P < 0.05). Venous compliance was less in patients compared with controls in the upper (P < 0.005) and lower extremities (P < 0.01) in the sympathetically activated state, but there were no differences at individual pressure levels. Sympathetic activation did not change venous compliance in the upper and lower extremity in patients and controls. Patients with orthostatic intolerance have reduced venous compliance in the lower extremity. Reduced compliance may limit the dynamic response to orthostatic change and thereby contribute to symptoms of orthostatic intolerance in this population group.