Factors Affecting Surfactant Responsiveness

There is a wide variability in the therapeutic responsiveness to exogenous surfactant, a drug that has become generally available for the treatment of lung immaturity and respiratory distress syndrome. Recent studies have demonstrated evidence that therapies decreasing lung edema improve the effectiveness of surfactant substitution. In addition, exogenous surfactant may acutely decrease pulmonary perfusion since the airway pressures are effectively transmitted to airspaces, compressing alveolar capillaries, especially in hypovolemia. Therapies aimed at decreasing lung edema, improving cardiac output, and stepwise weaning from oxygen and ventilatory pressures are cornerstones in the successful management of patients undergoing surfactant therapy.     

Surfactant inhibition of cholesterol oxidase

Little is known of the effect of surfactants upon the activity of cholesterol oxidase. This study demonstrates the interrelationship of surfactant, enzyme and substrate, and illustrates a possible source of inaccuracy within an enzymatic cholesterol assay.Using the rate at which cholesterol is converted to Δ⁴-cholestenone, the reaction was followed directly by monitoring the increase in absorbance at 240 nm. Inhibition of cholesterol oxidase was demonstrated with three surfactants, hydroxypolyethoxydodecane, Tween 20 and Triton-X-405. A fourth, Triton-X-100, produced high enzyme activity, although low concentrations resulted in incomplete substrate dispersal and high concentrations caused high blank values. Hydroxypolyethoxydodecane was studied more closely and the mechanism of inhibition is suggested as poor substrate dispersal at low surfactant concentration and a competitive inhibition at higher concentrations.     

Surfactant biology and clinical application

There is strong evidence that alterations in the pulmonary surfactant system play an important role in the pathophysiology of lung disease, including ARDS . Although it is still unclear whether mortality and morbidity of ARDS will be reduced, surfactant replacement therapy has been shown to improve oxygenation, improve lung compliance, and decrease the need for ventilatory support. The critical need for more standardized studies with one type of intratracheal surfactant and uniform measurements of surfactant proteins and phospholipids by BAL is evident. Further studies will also be needed to elucidate the optimal timing and dosage regimen for different disease processes. Some evidence supports the measurements of surfactant protein levels as markers for predicting the onset and outcome of ARDS and perhaps providing a window for early treatment of patients at risk to develop ARDS. Continued investigation into the role of surfactant in the immune regulation of the lung may also provide additional information to support the efficacy of surfactant replacement in lung disease.     

肺泡表面活性物质及其与支气管哮喘

肺泡表面活性物质(PS)为一种磷脂蛋白复合物,具有维持小气道通畅,防止黏液栓阻塞而降低气道阻力的作用。PS相对不足或功能不良,肺的顺应性下降,气道反应性增高,导致支气管哮喘发作。     

Surfactant: clinical applications.

Pulmonary surfactant is an important chemical component of the lung. It decreases surface tension in the alveolar cells to help stabilize the alveoli, and it may help prevent pulmonary edema. Currently, naturally and synthetically derived surfactants are being used to treat neonatal respiratory distress syndrome, a leading cause of death in premature infants. Surfactant is recommended for prophylactic therapy in infants weighing less than 1,350 g (3 lb) and in infants weighing more than 1,350 g who show signs of pulmonary immaturity and for rescue therapy in infants with respiratory distress syndrome. Surfactant is administered by endotracheal tube, and the recommended dose is 5 mg per kg. Three doses, given 12 hours apart, is the recommended regimen for prophylactic therapy. Rescue therapy consists of one dose of surfactant given at the onset of respiratory distress and another dose given 12 hours later.     

Surfactant protein D in human lung diseases

The lung is continuously exposed to inhaled pollutants, microbes and allergens. Therefore, the pulmonary immune system has to defend against harmful pathogens, while an inappropriate inflammatory response to harmless particles must be avoided. In the bronchoalveolar space this critical balance is maintained by innate immune proteins, termed surfactant proteins. Among these, surfactant protein D (SP-D) plays a central role in the pulmonary host defence and the modulation of allergic responses. Several human lung diseases are characterized by decreased levels of bronchoalveolar SP-D. Thus, recombinant SP-D has been proposed as a therapeutical option for cystic fibrosis, neonatal lung disease and smoking-induced emphysema. Furthermore, SP-D serum levels can be used as disease activity markers for interstitial lung diseases. This review illustrates the emerging role of SP-D translated from in vitro studies to human lung diseases.     

Surfactant phosphatidylcholine in thermally injured pigs.

OBJECTIVE: To investigate the effect of a thermal injury on pulmonary surfactant phosphatidylcholine kinetics. DESIGN: Random, controlled study. SETTING: University research laboratory. SUBJECTS: Yorkshire swine (n = 8) with and without a 40% total body surface area burn. INTERVENTIONS: A new isotope tracer methodology was used to quantify surfactant phosphatidylcholine kinetics. Four days after burn, [1,2-13C2]acetate and [U-(13)C16]palmitate were infused continuously for 8 hrs to quantify surfactant phosphatidylcholine synthesis, secretion, recycling, and irreversible loss. MEASUREMENTS AND MAIN RESULTS: The total surfactant phosphatidylcholine pool size was reduced from the control value of 2.65 +/- 0.05 to 1.61 +/- 0.08 micromol/g wet lung in burned animals (p <.05), as was the proportional contribution of palmitate to lung surfactant phosphatidylcholine composition. This reduction was associated with a significant decrease in lung dynamic compliance from the control value of 66 +/- 6 to 55 +/- 6 mL/cm H2O for burned pigs (p <.05). The most prominent response of lung phosphatidylcholine kinetics was a decrease in the total lung phosphatidylcholine synthesis from a control value of 12.7 +/- 1.2 to 5.5 +/- 0.3 nmol phosphatidylcholine-bound palmitate x hr(-1) x g of wet lung(-1) in burned animals (p<.05). CONCLUSIONS: Pulmonary phosphatidylcholine content and palmitate composition decrease after burn injury because of a decrease in the rate of phosphatidylcholine synthesis. These responses likely contribute to impaired lung compliance.     

Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production

Males have a higher morbidity and mortality for neonatal respiratory distress syndrome (RDS) than females, and respond less well to hormone therapy designed to prevent RDS by stimulating fetal pulmonary surfactant production. We have shown that male fetuses exhibit delayed production of pulmonary surfactant. We tested the hypothesis that the sex difference in fetal pulmonary surfactant production is under hormonal control. Pulmonary surfactant was measured as the saturated phosphatidylcholine/sphingomyelin ratio (SPC/S) in the lung lavage of fetal rabbits at 26 d gestation. There was an association between the sex of neighboring fetuses and the SPC/S ratio of the female fetuses, such that with one or two male neighbors, respectively, females had decreasing SPC/S ratios (P < 0.05). We injected dihydrotestosterone (DHT) into pregnant does from day 12 through day 26 of gestation in doses of 0.1, 1.0, 10, and 25 mg/d, and measured the SPC/S ratio in fetal lung lavage on day 26. In groups with the normal sex difference in fetal serum androgen levels (controls, 0.1 mg DHT/d) the normal sex difference in the SPC/S ratio was also present (females > males, P = 0.03). In the 1-mg/d group there was no sex difference in androgen levels and the sex difference in the SPC/S ratio was also eliminated as the female values were lowered to the male level. Higher doses of DHT (10, 25 mg/d) further reduced the SPC/S ratios. We injected the anti-androgen Flutamide (25 mg/d) from day 12 through day 26 of gestation. This treatment eliminated the normal sex difference in the lung lavage SPC/S ratio by increasing the male ratios to that of the females. We conclude that androgens inhibit fetal pulmonary surfactant production. An understanding of the mechanism of the sex difference in surfactant production may allow development of therapy that is as effective in males as in females for preventing RDS.     

含氟碳气体的表面活性剂类声学造影剂的体外实验

目的　研究含氟碳气体的表面活性剂类声学造影剂的基本特性。方法　将具有表面活性作用的司班 -80 和吐温 -80 按一定的体积比配制 ,加入 6 %低分子右旋糖酐溶液至 10ml,并将混合液充分搅拌 ;用声振仪振荡混合液 40s ,同时从注射器的底部匀速注入 10ml全氟丙烷气体。光镜 40 0倍下动态观察微气泡的浓度和直径 ,并运用体外循环系统观察不同剂量的彩色多普勒信号增强效果。结果　造影剂中微气泡的峰值浓度为 3.8× 10 9/ml,其中 90 %微气泡直径≤ 4.5 μm。体外模拟循环系统的能量多普勒信号增强持续时间随剂量增加而增加。结论　表面活性剂类声学造影剂的微气泡直径小、浓度高 ,且具有价格低廉、制作简单和明显增强多普勒信号的特点 ,值得进一步深入研究     

Surfactant protein A in bronchoalveolar lavage fluid.

We measured surfactant protein A and phosphatidylcholine in the bronchoalveolar lavage fluid from healthy volunteers and several groups of patients with lung diseases to obtain information on surfactant in the lung. We developed three types of enzyme-linked immunosorbent assays that used combinations of polyclonal antiserum and monoclonal antibodies. Phosphatidylcholine was assessed by enzymatic measurement. The median amounts of surfactant protein A in bronchoalveolar lavage fluid determined by the enzyme-linked immunosorbent assay with monoclonal antibodies were as follows: control subjects (n = 10), 2.82 mg/L (range, 0.92 to 5.17 mg/L); patients with asthma (n = 13), 1.89 mg/L (range, 0.45 to 2.95 mg/L); and patients with pulmonary sarcoidosis (n = 20), 2.98 mg/L (range, 0.68 to 7.02 mg/L). The median phosphatidylcholine concentrations in the bronchoalveolar lavage fluid were as follows: control subjects (n = 10), 20 mumol/L (range, 3 to 37 mumol/L); patients with asthma (n = 12), 24 mumol/L (range, 3 to 55 mumol/L); and patients with pulmonary sarcoidosis (n = 20), 26 mumol/L (range, 4 to 76 mumol/L). As a group, the patients with asthma had less surfactant protein A in bronchoalveolar lavage fluid than did the control subjects (Mann-Whitney U test, p less than 0.05). The surfactant protein A levels measured by the enzyme-linked immunosorbent assay with polyclonal antiserum and by a competitive enzyme-linked immunosorbent assay were also lower in bronchoalveolar lavage fluid from patients with asthma than in that from control subjects. The phosphatidylcholine concentrations in all groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

鹅膏毒肽染毒后大鼠肺表面活性物质的测定

【目的】实验观察鹅膏毒肽染毒后大鼠肺表面活性物质（PS）中磷脂（PL）的组分[磷脂酰甘油（PG）、磷脂酰肌醇（PI）、磷脂酰乙醇胺（PE）]和蛋白质含量的变化.寻找鹅膏毒肽中毒早期敏感特征性标志物.【方法】24只大鼠气管内滴注鹅膏毒肽（0.1 mg/kg,0.4 mg/kg）建立肺损伤模型.分别设12 h、2 d、3 d、5 d组.大鼠的肺组织块分别行HE染色电镜观察,测定支气管液中PL组分和蛋白质含量.【结果】实验组大鼠肺均可见PS层丧失连续、均匀的绒状结构,脱落入肺泡腔,以12 h组较明显.PS中PL（PG和PI）含量增加（P〈0.01）,以12 h组较明显.PS中蛋白质含量最高,以2 d组较明显.【结论】鹅膏毒肽中毒后PS的质与量的变化能较特异的反映肺损伤.测定PL含量是判断肺早期损伤的方法.PL中的PG和PI可能是鹅膏毒肽中毒早期敏感特征性标志物.     

Corticosteroids and Surfactant for Prevention of Neonatal RDS

Two main strategies are available for the prevention of neonatal respiratory distress syndrome (RDS) in cases of preterm delivery: antenatal administration of hormones that accelerate fetal lung maturation, and prophylactic treatment with surfactant soon after birth. The efficacy of each of these therapeutic regimens has been well documented in large randomized clinical trials, and recent data furthermore indicate that, in preterm babies with lowered risk of RDS after antenatal cortlcosteroid treatment, the odds for developing RDS are not further reduced by prophylactic treatment with surfactant. Corticosteroids and surfactant operate by clearly different mechanisms. The steroids stimulate (via the fibroblast-pneumonocyte factor) production of surfactant phospholipids by alveolar type II cells, enhance the expression of surfactant-associated proteins, reduce microvascular permeability, and accelerate overall structural maturation of the lungs. However, the increment in pool size of surfactant resulting from antenatal treatment with corticosteroids is trivial relative to the dose of exogenous surfactant required for successful prophylaxis at birth. Data from animal experiments indicate that antenatal corticosteroids and postnatal surfactant treatment have synergistic beneficial effects on neonatal lung function, and that these effects can be further potentiated by adding antenatal administration of thyrotrophin releasing hormone (TRH). Promising results have been obtained in recent clinical trials combining antenatal treatment with corticosteroids and TRH for prevention of RDS.     

Surfactant protein-A enhances respiratory syncytial virus clearance in vivo

To determine the role of surfactant protein-A(SP-A) in antiviral host defense, mice lacking SP-A (SP-A-/-) were produced by targeted gene inactivation. SP-A-/- and control mice (SP-A+/+) were infected with respiratory syncytial virus (RSV) by intratracheal instillation. Pulmonary infiltration after infection was more severe in SP-A-/- than in SP-A+/+ mice and was associated with increased RSV plaque-forming units in lung homogenates. Pulmonary infiltration with polymorphonuclear leukocytes was greater in the SP-A-/- mice. Levels of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were enhanced in lungs of SP-A-/- mice. After RSV infection, superoxide and hydrogen peroxide generation was deficient in macrophages from SP-A-/- mice, demonstrating a critical role of SP-A in oxidant production associated with RSV infection. Coadministration of RSV with exogenous SP-A reduced viral titers and inflammatory cells in the lung of SP-A-/- mice. These findings demonstrate that SP-A plays an important host defense role against RSV in vivo.     

Surfactant protein B deficiency in infants with respiratory failure

Surfactant Protein B (SP-B) deficiency has been recently identified as an uncommon, autosomal recessive lung disorder in term infants. This inability to produce SP-B leads to progressive, lethal, hypoxemic respiratory failure in the first year of life. A frameshift mutation (121 ins 2) is the predominant but not exclusive cause. The clue to diagnosis is to have a high suspicion of SP-B deficiency in any term infant with severe respiratory distress without any apparent cause. SP-B deficiency can be diagnosed prenatally or postnatally. The only current treatment options available include lung transplantation or compassionate care. Current developments in gene therapy offer hope for future treatment.