Cytokines in innate host defense in the lung.
Cytokines in innate host defense in the lung.
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DOI：
10.1172/jci15277
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发表时间：
2002-03
期刊：
影响因子：
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通讯作者：
R. Strieter;J. Belperio;M. Keane
中科院分区：
文献类型：
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作者：
R. Strieter;J. Belperio;M. Keane
历史上，肺一直被认为是一个主要参与气体交换的器官。然而，由于其与环境的独特关系，肺部必须保护自己免受大量吸入微生物的感染。各种先天防御保护肺部免受感染，包括咳嗽反射、粘膜纤毛清除（见Knowles和Boucher，本系列，参考文献1）和粘膜表面的抗菌特性（见Ganz，本系列，参考文献2；和McCormack和Whitsett，本系列，参考文献3）。此外，含有免疫和非免疫细胞的广泛肺泡毛细血管膜暴露于微生物挑战。因此，肺组织对吸入和血液病原体产生活跃的先天宿主反应，以清除有害微生物并保持气体交换。肺内先天防御反应的成功执行对适应性免疫的最终过渡和发展至关重要。一旦微生物被遏制，这种反应就会消退，导致修复或组织重塑。这些后期反应的丧失使肺部容易受到过度的局部或远处先天反应引起的组织损伤。在急性呼吸窘迫综合征等情况下，对微生物的过度组织炎症反应可能导致不可逆的肺损伤和死亡。虽然多种因素——花生四烯酸代谢物、凝血因子、补体、急性期蛋白和抗菌肽——都参与了先天反应，但细胞因子构成了这类介质中最大、最多元的一组，将成为本观点的重点。肺先天反应的启动、维持和解决依赖于细胞因子的细胞通讯。细胞因子与其他可溶性因子以及粘附分子一起，有助于病原体的识别，中性粒细胞和单核细胞的招募，以及入侵微生物的清除。细胞因子信号通过受体-配体在特定免疫或非免疫靶细胞群上的相互作用发生。这些种群的差异不仅在于它们的细胞因子受体的补体，而且还在于它们在特定刺激下精心制作和分泌特定细胞因子的能力。各种细胞群之间的相互作用导致了细胞因子网络的概念，其中一个细胞群可能直接对特定的外源性或内源性刺激作出反应，导致特定细胞因子的细化，对另一个细胞群施加不同的影响。靶细胞通过产生细胞因子来作出反应，细胞因子可以作为初始细胞的反馈信号，或者通过释放信号分子来影响另一组靶细胞。炎症效应细胞，如中性粒细胞和单核细胞，可能被局部募集和激活，以响应特定的趋化信号，导致非免疫驻留细胞进一步扩增细胞因子级联。
Historically the lung has been perceived as an organ primarily involved in gas exchange. However, due to its unique relationship with the environment, the lung must defend itself from infection by numerous inhaled micro-organisms. Various innate defenses protect the lung from infection, including the cough reflex, mucociliary clearance (see Knowles and Boucher, this Perspective series, ref. 1), and antimicrobial properties of the mucosal surface (see Ganz, this series, ref. 2; and McCormack and Whitsett, this series, ref. 3). In addition, an extensive alveolar-capillary membrane containing immune and nonimmune cells is exposed to microbial challenges. Consequently, pulmonary tissues generate a brisk innate host response to both inhaled and hematogenous pathogens in order to clear the offending micro-organism and preserve gas exchange. The successful execution of the innate defense response in the lung is critical to the eventual transition and development of the adaptive immunity. Once containment of the micro-organism has occurred, the response resolves, leading to repair or tissue remodeling. Loss of these later responses leaves the lung susceptible to tissue injury caused by excessive local or distant innate responses. In conditions such as acute respiratory distress syndrome, overexuberant tissue inflammation in response to micro-organisms may lead to irreversible lung injury and mortality. While a variety of factors — arachidonic acid metabolites, coagulation factors, complement, acute-phase proteins, and antimicrobial peptides among them — are involved in the innate response, cytokines constitute the largest and most pleiotropic group of such mediators and will be the focus of this Perspective. The initiation, maintenance, and resolution of pulmonary innate responses depend upon cellular communication via cytokines. Along with other soluble factors, as well as adhesion molecules, the cytokines contribute to the recognition of pathogens, the recruitment of neutrophils and mononuclear cells, and the removal of the invading micro-organism. Cytokine signaling occurs through receptor-ligand interactions on specific immune or nonimmune target cell populations. These populations differ not only in their complement of cytokine receptors, but also in their capacities to elaborate and secrete specific cytokines in response to particular stimuli. Interactions among various cell populations have led to the concept of cytokine networking, in which one population of cells may respond directly to specific exogenous or endogenous stimuli, leading to the elaboration of a particular cytokine that exerts distinct effects upon another population of cells. The targets respond by producing cytokines, which may serve as feedback signals to the initiating cell, or, alternatively, by releasing signaling molecules that affect yet another array of target cells. Inflammatory effector cells, such as neutrophils and monocytes, may be locally recruited and activated in response to specific chemotactic signals, resulting in further amplification of a cytokine cascade by nonimmune resident cells.