Granulocyte apoptosis and its role in the resolution and control of lung inflammation
Granulocyte apoptosis and its role in the resolution and control of lung inflammation
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DOI：
10.1164/ajrccm.160.supplement_1.4
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发表时间：
1999-11-01
影响因子：
24.7
通讯作者：
Haslett, C
中科院分区：
文献类型：
--
作者：
Haslett, C
阐明尚不清楚的急性炎症通常消退的机制，可能为了解炎症性疾病特征的持续炎症状态的发病机制提供新的见解，并产生新的治疗靶点。我们已经集中在机制，通过粒细胞和他们的组织毒性内容清除炎症部位在决议。尽管人们一直认为外渗的中性粒细胞在原位分解（经历坏死），但我们已经证明了另一种命运，即细胞经历凋亡，这一过程对炎症的控制具有不同的意义。在细胞凋亡过程中，中性粒细胞保留其颗粒内容物，并在分泌剂的作用下失去分泌颗粒内容物的能力。与坏死中性粒细胞相反，凋亡中性粒细胞被炎性巨噬细胞吸收，采用新的吞噬识别机制，不能引起巨噬细胞的促炎反应。这些识别机制可以被许多环境因素调节，并且可能代表炎症控制的关键点，因为如果凋亡的粒细胞不能迅速清除，它们会经历继发性坏死，并带来所有有害的后果。凋亡清除途径也适用于嗜酸性粒细胞，但我们的研究表明其内部控制可能与中性粒细胞不同。例如，皮质类固醇延缓中性粒细胞的凋亡，但大大加速嗜酸性粒细胞的凋亡，这可能代表了一种以前未被怀疑的类固醇作用在过敏性疾病（如支气管哮喘）中的有益机制。此外，这种差异可能导致基于特异性诱导嗜酸性粒细胞凋亡的新疗法。
Elucidation of the poorly understood mechanisms by which acute inflammation normally resolves is likely to provide new insights into the pathogenesis of persistent inflammatory states that characterize inflammatory disease and generate new therapeutic targets. We have concentrated on the mechanisms by which granulocytes and their histotoxic contents are cleared from inflamed sites during resolution. Although it had been assumed that extravasated neutrophils disintegrated (undergo necrosis) in situ, we have demonstrated an alternative fate, whereby the cell undergoes apoptosis, a process that has different implications for the control of inflammation. During apoptosis the neutrophil retains its granule contents and loses the ability to secrete them in response to secretagogues. In contrast to necrotic neutrophils, apoptotic neutrophils are ingested by inflammatory macrophages employing novel phagocytic recognition mechanisms that fail to provoke a macrophage proinflammatory response. These recognition mechanisms can be modulated by a number of environmental factors and may represent a pivotal point in the control of inflammation, since if apoptotic granulocytes are not rapidly cleared they undergo secondary necrosis with all the detrimental consequences entailed. The apoptotic clearance pathway is also available to eosinophil granulocytes, but our work suggests that the internal controls may be different from those in neutrophils. For example, corticosteroids delay neutrophil apoptosis but greatly accelerate eosinophil apoptosis, in what may represent a previously unsuspected beneficial mechanism of steroid action in allergic diseases such as bronchial asthma. Furthermore, such differences may lead to novel therapies based on the specific induction of eosinophil apoptosis.