SP—A、SP—D与肺部天然免疫防御

肺表面活性物质脱辅基蛋白A、D（SP－A、SP－D）系C型凝集素超家族中胶凝素家族成员，是肺部重要的天色免疫防御分子，不仅能清除病原体，还参与免疫、炎症及过敏反应的调节。     

肺泡外肺表面活性物质结合蛋白A研究进展

肺表面活性物质结合蛋白A(SP A)是肺表面活性物质中最主要的蛋白成分 ,主要由Ⅱ型肺泡上皮细胞及clara细胞分泌。研究发现 ,在肺泡外也存在相对低水平的SP A ,在传导气道、中耳、咽鼓管、鼻旁窦、胃肠道、生殖道、胸腺、脾脏、间皮及滑膜细胞内均可检测到SP AmRNA及蛋白 ,SP A可与病原及巨噬细胞结合 ,增强巨噬细胞吞噬杀灭病原 ,这些部位的SP A可能与宿主防御有关 ,在某些部位也有降低表面张力的作用     

050 肺表面活性物质相关蛋白A的免疫调节功能

肺表面活性物质相关蛋白A(SP-A)是肺表面活性物质相关蛋白中最重要的成分之一.作者概述了SP-A的分子结构与免疫的关系,以及对微生物、炎症细胞、炎症介质和抗体等的作用,提示SP-A具有广泛的免疫调节功能.最后提出一些值得研究的问题.     

肺表面活性物质相关蛋白A的免疫调节功能

肺表面活性物质相关蛋白A(SP A)是肺表面活性物质相关蛋白中最重要的成分之一。作者概述了SP A的分子结构与免疫的关系 ,以及对微生物、炎症细胞、炎症介质和抗体等的作用 ,提示SP A具有广泛的免疫调节功能。最后提出一些值得研究的问题     

目前我国对肺表面活性物质研究状况

肺表面活性物质(Pulmonary Surfactant)简称PS,是由肺泡Ⅱ型细胞合成和分泌的一种脂蛋白复合物,其主要成份是饱和卵磷脂,在肺泡气液界面上形成单分子膜.具有降低肺泡表面张力、稳定肺泡、减少呼吸功、维持正常肺功能等重要作用.国外对PS引起关注,并从事有关的研究是从50年代开始的.30多年来,对PS系统的组成、形态结构,化学成份、代谢过程、物理化学特征、生理功能、合成与分泌的调节、以及PS与各种呼吸疾病的关系等各方面作了深入的研究.特别是1980年Fujiware等人用从牛肺中提取的PS,经气管给10名肺透明膜患儿滴注治疗,患儿血氧发生明显改善.Fujiware等人这一研究工作的成功极大地鼓舞人们.这为PS用于临床闯出了一条新路.很快各国均报道     

疏水性肺表面活性物质蛋白的结构研究进展

疏水性肺表面活性物质蛋白(SP)包括SP-B和SP-C,它们在决定肺表面活性物质的结构、代谢及功能等方面有重要作用。SP-B和SP-C功能的多样性可能与其结构的特殊性有关,在表达及合成的过程中,二者的结构均经过了复杂的加工,使之能与脂质系统相互作用以发挥其生理功能。     

肺表面活性物质相关蛋白A的免疫调节功能

肺表面活性物质相关蛋白A（SP－A）是肺表面活性物质相关蛋白中最重要的成分之一。作者概述了SP－A的分子结构与免疫的关系,以及对微生物、炎症细胞、炎症介质和抗体等的作用,提示SP－A具有广泛的免疫调节功能,最后提出一些值得研究的问题。     

肺表面活性物质替代治疗新生儿肺透明膜病临床研究

目的分析肺表面活性物质治疗肺透明膜病(HMD)的疗效及临床价值.方法观察20例HMD患儿Exsurf治疗前后肺功能机械通气参数及肺泡充气程度的变化.结果用药前后PaO2、动脉-肺泡氧分压比值上升为44±15～93±44mmHg、0.11±0.05～0.22±0.04,PaO2、PaCO2、氧合指数、动脉-肺泡氧分压比值治疗前后比较差异均有非常显著性(p<0.01),用药后12h机械通气参数较治疗前明显下降(p<0.05～0.01),用药后12h胸片提示肺部病变明显改善.用药后肺炎,颅内出血并发症为70%和35%.结论 HMD 患儿Exsurf治疗后肺功能和肺泡充气程度明显改善.     

肺表面活性物质结合蛋白A研究进展

SP A是肺表面活性物质的重要蛋白成分 ,在维持PS内环境稳定和机体免疫方面发挥重要作用。最近研究表明 ,肺表面活性物质磷脂和SP A也存在于肺泡外肺组织及身体其它器官。就SP A受体、SP A基因表达调控、不同疾病时SP A水平变化及其在肺泡外组织中的分布与功能方面的相关研究进展作一简要综述。     

A Recombinant Fragment of Human Surfactant Protein D Lacking the Short Collagen‐Like Stalk Fails to Correct Morphological Alterations in Lungs of SP‐D Deficient Mice

Emphysema‐like pathology is a characteristic feature of surfactant protein D (SP‐D) knock‐out mice. Treatment with a recombinant fragment of human SP‐D consisting of a short collagen‐like stalk (but not the entire collagen‐like domain of native SP‐D), neck, and carbohydrate recognizing domain (CRD) inhibits development of emphysema‐like pathology in SP‐D deficient mice. On the other hand, it has been shown that the entire collagen‐like domain is necessary for preventing SP‐D knock‐out mice from pulmonary emphysema development. Thus, in the present study, we aimed to elucidate the role of the short collagen‐like stalk for the function of the recombinant fragment of human SP‐D. We treated SP‐D knock‐out mice with a fragment of human SP‐D lacking the short collagen‐like stalk and compared the effects on lung morphology with results from untreated wild‐type and SP‐D knock‐out mice and from SP‐D knock‐out mice treated with a recombinant fragment of human SP‐D including the short collagen‐like stalk. The fragment of SP‐D lacking the short collagen‐like stalk failed to correct pulmonary emphysematous alterations demonstrating the importance of the short collagen‐like stalk for the biological activity of the recombinant fragment of human SP‐D. Anat Rec, 2009. © 2008 Wiley‐Liss, Inc.     

Allergen-induced bronchial inflammation is associated with decreased levels of surfactant proteins A and D in a murine model of asthma

Background Increasing evidence suggests that pulmonary surfactant protein A (SP‐A) and D (SP‐D) participate in the lung defence against pathogens. However, the role of surfactant proteins in the pathogenesis of allergen‐induced airway inflammation has not been elucidated. In this study we examined the levels and distributions of SP‐A and SP‐D in a dust mite (Dermatophagoides pteronyssinus, Der p) allergen‐induced murine model of asthma. Methods The concentration of SP‐A and SP‐D in the bronchoalveolar lavage fluid (BALF) and the distribution of surfactant proteins in the lung were assayed by ELISA and immunohistochemistry methods, respectively. The effect of surfactant proteins on allergen‐induced pulmonary lymphocyte proliferation was also studied. Results We demonstrated that there were marked reductions of SP‐A and SP‐D levels in the BALF of Der p‐sensitized BALB/c mice at 48–72 h after allergen challenge (AC). Both purified SP‐A and SP‐D were able to suppress, in a dose dependent manner, Der p‐stimulated intrapulmonary lymphocyte proliferation of naïve mice with saline or allergen challenge, or of Der p‐sensitized mice with saline challenge. On the contrary, this suppressive effect was mild (< 9%) on lymphocytes from sensitized mice after AC. Conclusion These results indicated the involvement of pulmonary surfactant proteins in the allergic bronchial inflammation of sensitized mice.     

Localization of surfactant protein‐D in the rheumatoid synovial membrane

Surfactant protein‐D (SP‐D) is a collectin, which plays an important role in airway protection and inflammation. The molecule has both pro‐ and anti‐inflammatory capacities depending on its molecular size. Its involvement in joint diseases is largely unknown and the aim of this investigation was to study SP‐D occurrence and distribution in the synovial membrane of patients with long‐standing rheumatoid arthritis (RA) and osteoarthritis (OA). Six RA patients and six OA patients, who underwent total hip arthroplasty, were included in the study. Synovial tissue biopsies were obtained during surgery and subsequently prepared for immunohistochemistry. In this first, small‐scale comparative study on the occurrence of SP‐D in the synovial membrane of RA and OA, we report that SP‐D was only present in the microvascular endothelium in subsynovial and pannus tissue and that the immunostaining was much stronger than in OA. This distribution pattern suggests that SP‐D modulates RA inflammatory activities.     

肺表面活性蛋白D的研究进展

肺表面活性蛋白D(surfactant protein D,SP-D)在机体肺部防御和先天性免疫方面发挥着重要作用.目前的研究表明,SP-D参与多种肺部疾病的发生、发展,可以作为多种肺部疾病的生物标记.同时,表明SP-D可能成为治疗肺部炎症性疾病有效的治疗手段.     

Rare SP-A alleles and the SP-A1-6A(4) allele associate with risk for lung carcinoma

Next to cigarette smoking, genetic factors may contribute to lung cancer risk. Pulmonary surfactant components may mediate response to inhaled carcinogenic substances and/or play a role in lung function and inflammation. We studied associations between surfactant protein (SP) genetic variants and risk in lung cancer subgroups. Samples (n=308) were genotyped for SP-A1, -A2, -B, and -D marker alleles. These included 99 patients with small cell lung carcinoma (SCLC, n=31), or non-SCLC (NSCLC, n=68) consisting of squamous cell carcinoma (SCC, n=35), and adenocarcinoma (AC) (n=23); controls (n=99) matched by age, sex, and smoking status (clinical control) to SCLC and NSCLC; and 110 healthy individuals (population control). We found (a) no significant marker associations with SCLC, (b) rare SP-A2 (1A9) and SP-A1 (6A11) alleles associate with NSCLC risk when compared with population control, (c) the same alleles (1A9, 6A11) associate with risk for AC when compared with population (6A11) or clinical control (1A9), and (d) the SP-A1-6A4 allele (found in approximately 10% of the population) associates with SCC, when compared with population or clinical control. A correlation between SP-A variants and lung cancer susceptibility appears to exist, indicating that SP-A alleles may be useful markers of lung cancer risk.     

Influence of serum protein and albumin addition on the structure and activity of an exogenous pulmonary surfactant

The comparative analysis of the deleterious action of albumin and total serum proteins (SP) might help to understand the nature of the interaction surfactant--SP. This study evaluated the effects of serum proteins and albumin on bulk shear viscosity, surface tension, surface area reduction, and the ratio between the light and heavy subtypes of surfactant suspensions. Our results showed a correlation between the bulk viscosity and aggregation degree of surfactant suspensions. The addition of albumin or SP induced the transformation from the heavy to the light subtype, reducing the viscosity. SP caused disaggregation and inactivation, whereas albumin caused only disaggregation without loss of surface activity. When SP were removed, the heavy fraction obtained recovered its surface activity. We conclude that the disaggregation may not be the primary cause for the loss of surface activity. Surfactant inactivation by a serum component, different from albumin, would be probably due to a physical interaction, a phenomenon that is reversed when SP are removed.     

SP‐D and regulation of the pulmonary innate immune system in allergic airway changes

The airway mucosal surfaces are constantly exposed to inhaled particles that can be potentially toxic, infectious or allergenic and should elicit inflammatory changes. The proximal and distal air spaces, however, are normally infection and inflammation free due to a specialized interplay between cellular and molecular components of the pulmonary innate immune system. Surfactant protein D (SP‐D) is an epithelial‐cell‐derived immune modulator that belongs to the small family of structurally related Ca²⁺‐dependent C‐type collagen‐like lectins. While collectins can be detected in mucosal surfaces of various organs, SP‐A and SP‐D (the ‘lung collectins’) are constitutively expressed in the lung at high concentrations. Both proteins are considered important players of the pulmonary immune responses. Under normal conditions however, SP‐A‐/‐ mice display no pathological features in the lung. SP‐D‐/‐ mice, on the other hand, show chronic inflammatory alterations indicating a special importance of this molecule in regulating immune homeostasis and the function of the innate immune cells. Recent studies in our laboratory and others implied significant associations between changes in SP‐D levels and the presence of airway inflammation both in animal models and patients raising a potential usefulness of this molecule as a disease biomarker. Research on wild‐type and mutant recombinant molecules in vivo and in vitro showed that SP‐D binds carbohydrates, lipids and nucleic acids with a broad spectrum specificity and initiates phagocytosis of inhaled pathogens as well as apoptotic cells. Investigations on gene‐deficient and conditional over expressor mice in addition, provided evidence that SP‐D directly modulates macrophage and dendritic cell function as well as T cell‐dependent inflammatory events. Thus, SP‐D has a unique, dual functional capacity to induce pathogen elimination on the one hand and control of pro‐inflammatory mechanisms on the other, suggesting a potential suitability for therapeutic prevention and treatment of chronic airway inflammation without compromising the host defence function of the airways. This paper will review recent findings on the mechanisms of immune‐protective function of SP‐D in the lung. Cite this as: L. R. Forbes and A. Haczku, Clinical & Experimental Allergy, 2010 (40) 547–562.     

Reduced airway inflammation in CD26/DPP4‐deficient F344 rats is associated with altered recruitment patterns of regulatory T cells and expression of pulmonary surfactant proteins

Introduction CD26 is highly expressed on lung epithelial cells as well as on immune cells. Ovalbumin (OVA)‐induced airway inflammation induces a further increase of CD26 expression. CD26‐deficient rat strains exhibit blunted clinical courses in models of experimental asthma. Objective (1) To investigate the involvement of regulatory T cells (Tregs) and the surfactant system in a rat model of genetic CD26 deficiency. (2) To investigate regulatory mechanisms dependent on the endogenous CD26 expression. (3) To investigate the impact of CD26 on surfactant protein (SP)‐levels under inflammatory conditions. Methods Wild‐type and CD26‐deficient F344 rats were sensitized to and challenged with OVA. Subsequently, airway inflammation, SP levels as well as surface tension of the bronchoalveolar lavage (BAL) fluid were evaluated. Results CD26 deficiency led to decreased airway inflammation, e.g. reduced numbers of eosinophils and activated T cells in the BAL. Remarkably, the CD26‐deficient rats exhibited a significantly increased influx of FoxP3⁺ Tregs into the lungs and increased IL‐10‐secretion/production by draining lymph node cells in culture experiments. Furthermore, in OVA‐challenged CD26‐deficient rats, the increase of the expression of the collectins SP‐A and SP‐D as well as of the surface tension‐active SP‐B was significantly less pronounced than in the CD26‐positive strain. Only in the wild‐type rats, functional alterations of the surfactant system, e.g. the increased surface tension were obvious after OVA challenge. Conclusion Reduced airway inflammation in CD26‐deficient F344 rats appear to be mediated by differences in the recruitment and activity of Tregs. This altered inflammation is associated with differences in the SP expression as well as function. Cite this as: A. Schmiedl, J. Krainski, F. Schwichtenhövel, J. Schade, C. Klemann, K. A. Raber, K. Zscheppang, T. Beekmann, C. Acevedo, T. Glaab, D. Wedekind, R. Pabst, S. von Hörsten and M. Stephan, Clinical & Experimental Allergy, 2010 (40) 1794–1808.     

Surfactant protein D inhibits mite-induced alveolar macrophage and dendritic cell activations through TLR signalling and DC-SIGN expression

Background Surfactant protein D (SP‐D), a secreted pattern recognition molecule associated with pulmonary innate immunity, has been shown to mediate the clearance of pathogens in multiple ways. However, how SP‐D interacts with alveolar macrophages (AMs) and dendritic cells (DCs) during allergen exposure remains unclear. Objective This study was performed to characterize the immunomodulatory effects of SP‐D on mite allergen (Dermatophagoides pteronyssinus, Der p)‐induced inflammatory signalling in AMs and DCs. Methods Murine AM, alveolar macrophage cell line derived from BALB/c mice (MH‐S cells), and human monocyte‐derived dendritic cells (MDDC) were used as model systems. The production of nitric oxide (NO) and TNF‐α, expression of surface Toll‐like receptors (TLRs), and expression of the C‐type lectin receptor known as dendritic cell (DC)‐specific ICAM‐grabbing non‐integrin (DC‐SIGN) were measured as a function of pretreatment with SP‐D and subsequent exposure to Der p. Der p‐dependent cellular activations that were modified by SP‐D in these model systems were then identified. Results Pretreatment of MH‐S cells with SP‐D reduced Der p‐dependent production of NO, TNF‐α, and the downstream activations of IL‐1 receptor‐associated kinase, mitogen activated protein kinase (MAPK) kinase, and nuclear factor‐κB. SP‐D interacted with CD14 such that CD14 binding to Der p was inhibited and Der p‐induced signalling via TLRs was blocked. DC‐SIGN expression was suppressed by Der p in MH‐S and MDDC; this down‐regulation of DC‐SIGN expression was prevented by pretreatment with SP‐D. Conclusions These results indicated that the inhibition of Der p‐induced activation of MH‐S and MDDC by SP‐D is mediated through suppression of the CD14/TLR signalling pathway and maintenance of DC‐SIGN expression, which may protect allergen‐induced airway inflammation. Cite this as: C‐F Liu, M. Rivere, H‐J Huang, G. Puzo and J‐Y Wang, Clinical & Experimental Allergy, 2010 (40) 111–122.     

Interaction of human lung surfactant proteins A and D with mite (Dermatophagoides pteronyssinus) allergens

Human lung surfactant proteins A (SP-A) and D (SP-D) are both collagenous C-type lectins which appear to mediate antimicrobial activity by binding to carbohydrates on micro-organisms and to receptors on phagocytic cells. Purified native SP-A and SP-D, isolated from human bronchoalveolar lavage fluid, were found to bind to whole mite extracts (Dermatophagoides pteronyssinus) and the purified allergen Der p I, in a carbohydrate-specific and calcium-dependent manner. Binding was inhibited by ethylenediamine tetra-acetic acid (EDTA) as well as by maltose in the case of SP-D, or mannose in the case of SP-A. A recombinant polypeptide, which trimerized to form the neck region and carbohydrate recognition domains of SP-D, also inhibited the binding of native SP-D to the whole mite extract and Der p I. Both SP-A and SP-D did not bind to deglycosylated whole mite extracts or to recombinant Der p proteins, which lacked carbohydrate residues. These results suggest that the ability of surfactant proteins to bind certain allergens is mediated through their carbohydrate-recognition domains (CRDs) interacting with carbohydrate residues on the allergens. Moreover, SP-A and SP-D were found to inhibit allergen-specific IgE binding to the mite extracts either via steric hindrance or competitive binding. It is therefore possible that SP-A and SP-D may be involved in the modulation of allergen sensitization and/or the development of allergic reactions.