脂多糖(LPS)是革兰氏阴性细菌外膜的主要组成部分。LPS是炎症最有效的微生物诱导剂之一,是肺部感染的许多有害作用的原因。相反,身体的表面不断暴露于少量的LP。这种相互作用似乎刺激了更有益的保护机制。总体而言,LPS与身体之间的相互作用很重要。但是,确定此反应性质的因素尚不清楚。
LPS is a prototypical pathogen associated molecular pattern (PAMP), a term that was introduced by Janeway and Medzhitov1,描述了微生物的结构保守分子。PAMP与先天免疫系统的受体结合,因此称为模式识别受体(PRR)。1996年,果蝇蛋白质损失被证明是蝇对真菌进行有效免疫反应所必需的Aspergillus fumigatus。In 1998, toll like receptor (TLR)4 was positionally identified as the LPS receptor and found to be required for mice to effectively respond to Gram-negative bacteria. These findings have guided the field of (innate) immunity over the last few years. Thirteen mammalian TLR analogues have been identified and functionally linked to various processes, ranging from inflammation and infection, to arthrosclerosis and sterile inflammation2。
In the lung, TLR4 is expressed by several different cell types, including professional host defence (dendritic cells, macrophages) and structural (endothelial and epithelial cells) cells. Animal models and patient studies have proved that TLR4 contributes significantly to the response to inhaled LPS3,4。It is obvious that high levels of LPS initiate a host defence reaction with subsequent activation of the adaptive immune system. Interestingly, low levels of LPS also appear to influence the biology of the lungs. The respiratory tract is constantly exposed to LPS contained in cigarettes, bedcovers or elsewhere. Epidemiological evidence suggests that the level of inhaled LPS during early childhood determines susceptibility to allergic airway disease5。The presence of bacterial PAMPs such as LPS and its recognition by epithelial cells is important for tissue homeostasis in the gastrointestinal tract6。LPS obviously serves not only as an exogenous danger signal, but also as a beneficial exogenous compound modulating processes such as adaptive immunity or tissue repair.
Taken together, the interaction of LPS and the lung is important and complex. Experimental information is needed from a number of different levels. This issue of the欧洲呼吸杂志contains two papers that characterise the interaction of LPS and the lung. The first study addresses the mechanisms that are involved in the pulmonary response to LPS exposure. The study of Eutameneet al.7研究了肌球蛋白轻链激酶(MLCK)在对呼吸道应用的LPS反应中的作用。作者参与了大鼠动物模型,并使用组织培养技术进一步阐明了细胞机制。MLCK活性主要与气道平滑肌或内皮细胞的生物学联系在一起8, but also to epithelial permeability9。科学家使用特定的MLCK抑制剂ML-7。来自动物实验的数据表明,ML-7抑制了LPS引起的嗜中性炎症。体外ML-7抑制LPS暴露后MLCK的磷酸化。这些数据提供了证据,表明肺部紧密连接的调节对于炎症反应和炎症细胞的流入很重要。对于许多疾病,例如哮喘或COPD等经典炎症性疾病,尚未解决此问题。确定MLCK激活是否涉及经典识别机制或信号通路是否涉及,这将很有趣。有证据表明,除了CD14 -TLR4复合物之外,其他膜蛋白还可能参与LPS的识别。
The second study applied a human model of LPS exposure. There are only a small number of studies that have investigated the response of healthy volunteers to exposure with LPS. On the one hand, this type of study is very important because it is the ultimate goal in the understanding of the processes in the human lung. On the other hand, these studies are difficult to interpret because they are necessarily limited in the number of probands, and the effect of LPS certainly depends on dose, age of the probands, route of administration, duration of exposure and many other factors. The study of Roos-Engstrandet al.10研究了健康志愿者中肺对吸入LPS暴露的反应。作者分析信号级联并关注气道上皮。他们发现p38 MAPK的表达显着增加,p38 MAPK是炎症反应中中心位置的信号分子。IL-8和其他细胞因子没有显示重大变化。基于从患者或概率获得的材料,用于表征的方法受到限制。本研究采用了研究细胞内信号传导的复杂方法。由于许多信号分子被磷酸化或其他转录后修饰激活,因此必须使用适当的检测这些变化的工具。在本研究中,作者使用针对信号分子的磷酸化形式的抗体,并采用精致的定量方法。然而,要解决信号过程的形态学研究方法论很具有挑战性。
Both studies provide important data from different levels in the interaction between LPS and the lung. The complexity of the interaction between LPS and the body is reflected by the multitude of signalling pathways that have been described to be activated by LPS. The TLR/interleukin-1 receptor pathway is certainly one of the most prominent and is localised very proximally. Downstream signalling involves mitogen-activated protein kinases (MAPK), such as p38, described in one of the studies in this issue. The MAPK pathways transduce a large variety of external signals, leading to a wide range of cellular responses, including growth, differentiation, inflammation and apoptosis. Many questions have to be addressed to further clarify the relationship between LPS and the lungs in order to apply this knowledge in medicine.
1) What are the key cells that regulate the response to LPS? It is obvious that airway and parenchymal epithelial cells contribute significantly to the inflammatory response, but are they alone capable of recognising LPS? Experimental evidence suggests that macrophages are important in the initial recognition of LPS and then trigger epithelial cells.
2) Is the application of LPS equivalent to exposure to other PAMPs or even viable bacteria? The innate immune system is equipped with many PRRs and is probably capable of discriminating between different classes of microorganisms.
3)是剂量和时机(急性相对chronic) important? Almost certainly, yes. It has also been shown that different levels of LPS cause inhibition or stimulation of T-helper 2-weighted responses11。
4)有限合伙人暴露的结果总是损害al or can it, in some situations, be beneficial? It would be surprising if the body was unable to somehow deal with small amounts of LPS. This exposure was constantly present during the evolution of智人。The task is now to clarify whether this low level exposure has a role in pulmonary diseases.
5) What are the mechanisms of LPS recognition? Is it all based on TLRs or are other mechanisms involved? Surprisingly, neither article apply the TLR concept to their experimental set-up.
6)可以针对先天免疫系统或某些组件的信号通路来防止LPS识别的有害后果,从而使宿主防御机制完好无损?对各种信号通路及其平衡的详细理解是必要的12。
脂多糖与肺之间的相互作用对于健康和疾病很重要。必须在矩阵中填写更多数据点,以进一步了解这种复杂的交互。
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