Surfactant protein-D and surfactant inhibit endotoxin-induced pulmonary inflammation

BACKGROUND: Acute lung injury is a common cause of morbidity and mortality following pulmonary or systemic infections. Surfactant protein-D is a member of the collectin family of proteins, which play important roles in innate host defense of the lung. In this study, the effect of exogenous recombinant human SP-D (rhSP-D) on protection of the adult mouse lung from lipopolysaccharide (LPS)-induced and lipoteichoic acid (LTA)-induced injury was assessed. METHODS: The effect of rhSP-D on LPS-induced and LTA-induced lung inflammation and injury was assessed with and without exogenous pulmonary surfactant in Sftpd+/+ and Sftpd-/- mice. A total of 204 mice (6 mice per group) were used for the present study. RESULTS: Sftpd-/- mice were more susceptible to intratracheal LPS than were Sftpd+/+ mice. rhSP-D decreased neutrophilic infiltrates induced by LPS and LTA in the lungs of both Sftpd+/+ and Sftpd-/- mice. The addition of exogenous pulmonary surfactant to rhSP-D further decreased LPS-induced and LTA-induced pulmonary inflammation in Sftpd-/- and Sftpd+/+ mice. CONCLUSIONS: Intratracheal rhSP-D inhibited inflammation induced by intratracheal LPS and LTA instillation in the lung. The antiinflammatory effects of rhSP-D were enhanced by the addition of pulmonary surfactant, providing a potential therapy for the treatment of lung inflammation.     

肺表面活性物质治疗早产儿呼吸窘迫综合征给药时间的研究概况

肺表面活性物质(pulmonary surfactant,PS)已常规用于新生儿呼吸窘迫综合征的防治,其疗效肯定,并有大量文献报道其使用效果、给药方式、使用剂量等临床研究。但关于PS最佳给药时间的研究不多,给药时间与给药目的紧密相关,主要有早期的预防性给药、中期的替代治疗抢救性给药、晚期的挽救性给药和重复给药,因我国医疗发展的客观条件、治疗理念差别等因素在使用PS的时间界点上各有报道,该文对PS治疗早产儿呼吸窘迫综合征给药时间的研究情况作一概述。     

Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants.

Although surfactant deficiency at birth is the major cause of respiratory distress syndrome (RDS), there is insufficient data on surfactant and surfactant inhibitors after birth. In the present study, a total of 345 airway specimens (AS) from 61 neonates of gestational age of 24 to 29 wk (54 with RDS) were analyzed for concentrations of phosphatidylcholine (PC), saturated PC (SPC), surfactant protein A (SP-A), nonsedimentable protein, and free amino acids in epithelial lining fluid (ELF). The relationship between surfactant indices, surface activity, and severity of RDS was studied. Treatment with human surfactant containing SP-A increased [PC]ELF and [SPC]ELF to levels found in infants without RDS. In placebo-treated infants similar concentrations were first reached between Days 4 and 7. Surfactant treatment increased the low SP-A/SPC ratio, although this ratio remained lower than that in exogenous surfactant. In RDS, the concentrations of free amino acids in ELF were 6 to 31 times higher than in infants without RDS. The nonsedimentable proteins of AS and cationic amino acids increased the minimum surface tension of SP-A-deficient surfactant from AS. Addition of SP-A improved the surface activity. According to multiple regression analysis, In [PC]ELF (p less than 0.0001), SPC/PC ratio (p less than 0.0001), In SP-A/SPC ratio (p less than 0.0002), and [protein]ELF (p less than 0.01) correlated with alveolar-arterial oxygen pressure gradient. Of the infants weighing less than 1,000 g, those who were going to die or develop bronchopulmonary dysplasia had a strikingly lower SP-A/SPC ratio during the first week (less than 25 ng/nmol) than those surviving without BPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

急性肺栓塞大鼠肺表面活性物质的变化

目的探讨急性肺栓塞大鼠肺表面活性物质的变化情况。方法32只雄性SD大鼠以随机数字表法分为对照组、栓塞24h组、栓塞1周组、栓塞2周组,每组8只;以明胶海绵溶液经大鼠颈静脉注入制备大鼠肺栓塞模型,经右心导管测定肺动脉压、心率、呼吸频率,并行动脉血气分析。上述4组大鼠分别于肺动脉栓塞后2周、24h、1周、2周时处死,取肺组织制备病理切片,HE染色光镜下观察肺组织病理变化;逆转录聚合酶链反应、Western-blot法测定肺表面活性物质相关蛋白A(SPA)mRNA及蛋白水平。结果对照组、栓塞24h组、栓塞1周组、栓塞2周组大鼠肺动脉压平均值分别为(14.2±4.1)、(26.1±7.5)、(26.1±6.8)、(29.0±8.2)mm Hg(1mm Hg=0.133kPa),肺栓塞后大鼠肺动脉压升高(F值为3.09,P<0.05);心率分别为(415±15)、(451±35)、(463±29)、(446±14)次/min(F值为2.24,P<0.05);动脉血氧分压分别为(94.1±8.8)、(80.5±5.8)、(80.4±13.8)、(73.4±14.3)mm Hg(F值为1.25,P<0.05)。实验大鼠肺组织病理切片光镜检查,栓塞24h组可见肺组织多个血管腔有明胶海绵栓塞,栓塞1周组栓子部分溶解,栓塞2周组栓子基本溶解。大鼠肺栓塞后2周内肺组织SPA mRNA及蛋白水平显著下降,对照组、栓塞24h组、栓塞1周组、栓塞2周组肺组织SPA mRNA水平分别为1.43±0.51、0.83±0.33、0.91±0.33、0.87±0.35(F值为2.92,P<0.05);蛋白水平分别为1.00±0.00、0.44±0.18、0.44±0.33、0.52±0.32(F值为3.49,P<0.05)。结论大鼠急性肺栓塞后SPA水平显著降低,这可能与急性肺栓塞大鼠动脉低氧血症的发生有关。     

不同剂量国产牛肺表面活性物质治疗早产儿呼吸窘迫综合征疗效观察

目的评价不同剂量国产牛肺表面活性物质治疗早产儿呼吸窘迫综合征临床疗效及安全性。方法采用国产牛肺表面活性物质三种剂量治疗早产儿呼吸窘迫综合征的患儿,其中符合入选标准研究对象共93例。随机分为小剂量组(40-70 mg/kg,31例)、中剂量组(70-100 mg/kg,31例)和大剂量组(100-140 mg/kg,31例),比较三组患儿用药前后血气分析(p H,Pa O2,Pa CO2)的变化情况,记录三组患儿的性别、胎龄、出生体重、分娩方式、Apgar评分、羊水情况、有无胎膜早破、需重复用药例数、需机械通气例数、需机械通气时间、氧疗时间、住院天数、转归、并发症及平均住院费用等,进行统计分析。结果三组患儿比较性别、胎龄、出生体重、分娩方式、Apgar评分、羊水情况、有无胎膜早破等差异均无统计学意义(P0.05)。三组患儿首次应用肺表面活性物质治疗6 h后p H值及Pa O2均有不同程度升高、Pa CO2均有不同程度降低,与治疗前比较差异均有统计学意义(P0.05)。治疗前三组之间p H值、Pa O2及Pa CO2差异均无统计学意义(P0.05)。三组患儿之间比较治疗效果(需重复用药例数、需机械通气例数、需机械通气时间、氧疗时间)的差异均无统计学意义(P0.05)。三组之间比较并发症发生率及治愈率差异均无统计学意义(P0.05)。三组患儿之间比较平均住院天数及平均住院费用的差异有统计学意义(P0.05),中剂量组与大剂量组比较患儿的平均住院费用减少,与小剂量组比较患儿的平均住院天数减少。结论三种剂量国产牛肺表面活性物质治疗早产儿呼吸窘迫综合征均具有相似的临床疗效及安全性,但中剂量组与大剂量组比较可有效降低患儿的平均住院费用,与小剂量组比较可有效减少患儿的平均住院天数。     

吸入NO对婴幼儿体外循环中肺表面活性物质的影响

目的: 探讨吸入一氧化氮(NO)对婴幼儿体外循环（cardiopulmonary bypass,CPB）中肺表面活性物质的影响。 方法: 将30例患室间隔缺损的婴幼儿随机分为对照组和NO组,NO组在CPB期间吸入40 μl/L NO直至关胸。CPB前、主动脉开放后1,5,10 min以少量生理盐水灌洗气道,分别测定气道吸出物(BAL)中总磷脂(TPL)、饱和卵磷脂(SatPC)、总蛋白(TP)值,并计算SatPC/TPL和SatPC/TP。结果: CPB后两组SatPC/TPL、SatPC/TP较CPB前明显降低(P<0.01)。NO组SatPC/TPL和SatPC/TP下降的幅度明显小于对照组(P<0.01)。结论: 婴幼儿CPB术中存在明显的肺损害,表现为一些亚临床性肺功能损伤。吸入40 μl/L的NO对CPB期间肺功能有明显的保护作用。     

Surfactant protein A detection in primary pulmonary adenocarcinoma without bronchioloalveolar pattern

BACKGROUND: Immunohistochemical studies in human lung carcinoma reported positive staining of tumor cells for surfactant protein A (SP-A), especially in peripheral airway cell carcinoma, which include bronchioloalveolar carcinoma and in some reports also papillary subtypes. OBJECTIVE: The purpose of this study was to determine the SP-A expression in tumor cells of lung adenocarcinoma without a bronchioloalveolar pattern, classified according to the WHO. METHODS: In total, 169 primary adenocarcinomas of the lung (109 acinar, 32 solid with mucin, 24 papillary and 4 mucinous) were examined by immunohistochemistry for SP-A expression. RESULTS: Twenty-five percent of acinar, 38% of papillary and 3% of solid adenocarcinoma with mucin showed a positive intracytoplasmic SP-A reaction of the tumor cells. None of the mucinous adenocarcinomas stained for SP-A. This study included the largest number of acinar adenocarcinomas and solid adenocarcinomas with mucin studied for SP-A. We clearly demonstrated that also primary lung adenocarcinoma without a bronchioloalveolar pattern can express SP-A. A positive staining of hyperplastic type II cells surrounding the tumors or entrapped in the tumor could clearly be differentiated from the SP-A-positive stain of tumor cells. CONCLUSION: These results support the theory that SP-A-producing cells may generate not only bronchioloalveolar and papillary carcinoma, but also other subtypes of lung adenocarcinoma.     

Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency

RATIONALE: ABCA3 mutations are known to cause fatal surfactant deficiency. OBJECTIVE: We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis. METHODS: Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting. RESULTS: ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively. CONCLUSION: Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.     

Elevated serum surfactant protein A and D in pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by widespread localization of calcispherites in the alveolar spaces. The authors report two cases of PAM, with markedly elevated sera concentrations of surfactant protein-A and surfactant protein-D, which showed a tendency to increase as the disease progressed. Therefore, surfactant protein-A and surfactant protein-D may function as serum markers to monitor the disease activity and progression of PAM.     

肺表面活性物质相关蛋白A与D在肺结核诊断中的研究

目的 研究肺表面活性物质相关蛋白A、D（pulmonary surfactant associated protein A、D,SP-A、SP-D）在肺结核患者中的表达，探讨2者的相关性。 方法 采用ELISA方法检测涂阳肺结核50例，涂阴肺结核51例，慢性阻塞性肺疾病（COPD）患者30例及健康人85名血清及痰液中SP-A、SP-D的表达情况。 结果 涂阳肺结核组痰液中SP-A、SP-D的表达与痰液中结核分枝杆菌的含菌量有相关性；血清SP-A、SP-D在肺结核组高表达（P<0.05），痰SP-D在肺结核组低表达（P<0.01）。 结论 SP-A、SP-D的表达与肺结核之间可能有相关性，或可成为协助肺结核诊断的辅助指标。     

吸入一氧化氮对婴幼儿体外循环中肺功能及肺表面活性物质的影响

目的探讨吸入一氧化氮（NO）对婴幼儿体外循环中肺功能及肺表面活性物质的影响。方法将30例室间隔缺损患儿随机分为对照组和NO组。NO组在体外循环期间吸入40ppmNO直至关胸。体外循环前和术后气管插管未拔前0-1h,1-2h,2-3h测定气道压、吸入氧浓度和呼气末二氧化碳浓度（ETCO2）,并分别在同时点采动脉血进行血气分析,计算肺泡死腔率（VD／VT）、肺泡动脉血氧分压差（P（A—a）O2）、动脉血氧含量（CaO2）和肺泡氧合指数（OI）,记录术后呼吸机支持时间。体外循环前、主动脉开放后1、5、10min以少量生理盐水灌洗气道,分别测定气道吸出物（BAL）中总磷脂（TPL）、饱和卵磷脂（SatPC）、总蛋白（TP）值,计算SatPC／TPL（％）、SatPC／TP（mg／g）。结果与对照组相比,NO组VD／VT、P（A—a）O2、OI明显下降（0．43±0．22比0．73±0．16,81．9±31．6比102．6±36．4,1．25±0．12比1．89±0．13,P〈0．01）,CaO2升高（16.31±1．57比14．16±1．58,P〈0．01）;两组的SatPC／TPL、SatPC／TP,CPB后较CPB前明显降低（25．81±4．1比46．3±5．16,20．14±7．42比61．05±6．17,35．51±5．1比43．90±4．61,30．14±4．42比58．92±6．92,P〈0．01）。NO组SatPC／TPL和SatPC／TP下降的幅度明显小于对照组（47．52±2．75比（37．72±3．71,51．67±6．07比40．87±7．07,P〈0．01）。结论婴幼儿体外循环术中存在明显的肺损害,表现为一些亚临床性肺功能损伤。吸入40ppmNO对体外循环期间肺功能有保护作用。     

Markers of pulmonary inflammation in tracheobronchial fluid of premature infants with respiratory distress syndrome

To asses the role of pulmonary inflammation in the outcome of preterm neonates with respiratory distress syndrome (RDS) we measured soluble intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and transforming growth factor beta-1 (TGF beta 1) in tracheobronquial lavage (TBL) fluid of 15 preterm infants; 9/15 completely recovered from RDS and 6/15 developed chronic lung disease (CLD). ICAM-1 (p: 0.001) and TGF beta 1 (p: 0.04) levels increased in TBL fluid during the first days of life. The values of ICAM-1 were correlated to the days of 0(2) and mechanical ventilation dependency. At 3 days of age, ICAM-1 levels in TBL fluid were higher in infants who later developed CLD compared to infants without CLD (24.5 vs 8.3 micrograms/ml; p: 0.02). Thereafter no significant differences were found although the CLD group had higher values. IL-8 levels showed a fall, specially from 1 to 3 days of age in children without CLD (77.0 to 41.7 ng/ml) although not significant. No difference in TGF beta 1 values were found between both groups, but the TGF beta 1 levels were lower in patients with CLD and they showed undetectable values in 8 samples. ICAM-1 is a major factor associated with airways inflammation whereas IL-8 is not a good marker during the first days of life to predict the RDS outcome. A defect of TGF beta 1 in the smallest premature infants may delay the lung repair process which occurs after tissue injury. High ICAM-1 levels and low TGF beta 1 levels in lung fluid are related to oxygen dependency at 28 days of age.     

Lung expansion in premature newborn rabbits treated with emulsified synthetic surfactant; principles for experimental evaluation of synthetic substitutes for pulmonary surfactant

This paper presents a sequence of tests for experimental evaluation of potential substitutes for pulmonary surfactant. Differential thermal analysis and the pulsating bubble technique were applied to identify an emulsified mixture of synthetic lipids with properties similar to those of natural surfactant. Instilled into the airways of premature newborn rabbits, this emulsion improved pulmonary pressure-volume characteristics and enhanced lung-thorax compliance during artificial ventilation. However, the in vivo effect was inferior to that of natural surfactant, especially as the emulsion failed to prevent the development of bronchiolar epithelial lesions.     

Role of pulmonary surfactant protein D in innate defense against Candida albicans

Pulmonary surfactant protein D (SP-D), which is a member of the collectin family, is implicated in pulmonary defense against pathogens. To determine whether SP-D is involved in first-line immunity against Candida albicans, an important respiratory fungus, the interaction of SP-D with C. albicans was studied. SP-D was found to bind C. albicans, resulting in agglutination of the microorganisms. Binding was calcium dependent and was inhibited by competing sugars maltose or mannose. Incubation of C. albicans with SP-D resulted in profound fungal growth inhibition and decreased hyphal outgrowth. Furthermore, it was found that SP-D inhibited phagocytosis of C. albicans by alveolar macrophages. These data suggest that the lung collectin SP-D has an important role in first-line defense against C. albicans in the lung, by agglutinating C. albicans and limiting their growth, without the need for macrophage activation.     

Surfactant therapy improves pulmonary function in infants with Pneumocystis carinii pneumonia and acquired immunodeficiency syndrome

Pneumocystis carinii pneumonia (PCP) is an important cause of acute respiratory failure in HIV-infected children. PCP may initiate acute respiratory distress syndrome (ARDS) by adversely affecting surfactant physiology. We report improved pulmonary function following administration of bovine lipid extract surfactant to two infants with AIDS-related PCP/ARDS. Pediatr. Pulmonol. 1997; 24:370–373. © 1997 Wiley-Liss, Inc.