Decreased alveolar macrophage apoptosis is associated with increased pulmonary inflammation in a murine model of pneumococcal pneumonia.
Decreased alveolar macrophage apoptosis is associated with increased pulmonary inflammation in a murine model of pneumococcal pneumonia.
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DOI：
10.4049/jimmunol.177.9.6480
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发表时间：
2006-11-01
期刊：
影响因子：
--
通讯作者：
Dockrell DH
中科院分区：
文献类型：
--
作者：
Marriott HM;Hellewell PG;Cross SS;Ince PG;Whyte MK;Dockrell DH
炎症浸润的调节对于肺炎的成功结局至关重要。肺泡巨噬细胞凋亡是肺炎球菌感染和艾滋病疾病消退的特征。然而，巨噬细胞凋亡在对细菌感染的先天反应期间对宿主的益处还不完全确定。由于一氧化氮是所需的最佳巨噬细胞凋亡在肺炎球菌感染，我们已经探讨了巨噬细胞凋亡的作用，在肺炎球菌肺炎的炎症反应的调节，使用诱导型一氧化氮合酶（iNOS）缺陷小鼠。与野生型C57 BL/6小鼠相比，iNOS-/-小鼠在肺炎球菌攻击后表现出凋亡肺泡巨噬细胞数量减少。与此相关，iNOS-/-小鼠表现出更多的中性粒细胞聚集到肺中，TNF-α的表达增强。iNOS的药理学抑制产生了类似的结果。在iNOS-/-小鼠中，更大的肺部炎症与更高水平的早期菌血症、IL-6产生、肺部炎症和前48小时内的死亡率相关。标记的凋亡肺泡巨噬细胞被肺中的驻留巨噬细胞吞噬，并且肺内滴注外源性凋亡巨噬细胞减少了iNOS-/-小鼠中的中性粒细胞募集，降低了肺中的TNF-α mRNA和支气管肺泡灌洗液中的蛋白质，以及趋化因子和细胞因子（包括IL-6）。这些变化与小鼠发生菌血症的可能性较低有关。这证明了凋亡巨噬细胞下调炎症反应的潜力，并首次在体内证明了凋亡巨噬细胞的清除减少了肺炎期间的中性粒细胞募集和侵袭性细菌疾病。
Regulation of the inflammatory infiltrate is critical to the successful outcome of pneumonia. Alveolar macrophage apoptosis is a feature of pneumococcal infection and aids disease resolution. The host benefits of macrophage apoptosis during the innate response to bacterial infection are however incompletely defined. Since nitric oxide is required for optimal macrophage apoptosis during pneumococcal infection, we have explored the role of macrophage apoptosis in regulating inflammatory responses during pneumococcal pneumonia, using inducible nitric oxide synthase (iNOS)-deficient mice. iNOS-/- mice demonstrated decreased numbers of apoptotic alveolar macrophages as compared to wild-type C57BL/6 mice following pneumococcal challenge. In association with this, iNOS-/- mice demonstrated greater recruitment of neutrophils to the lung and enhanced expression of TNF-α. Pharmacologic inhibition of iNOS produced similar results. Greater pulmonary inflammation was associated with greater levels of early bacteremia, IL-6 production, lung inflammation and mortality within the first 48 h in iNOS-/- mice. Labelled apoptotic alveolar macrophages were phagocytosed by resident macrophages in the lung and intratracheal instillation of exogenous apoptotic macrophages decreased neutrophil recruitment in iNOS-/- mice and decreased TNF-α mRNA in lungs and protein in bronchial alveolar lavage, as well as chemokines and cytokines including IL-6. These changes were associated with a lower probability of mice becoming bacteremic. This demonstrates the potential of apoptotic macrophages to downregulate the inflammatory response and for the first time in vivo demonstrates that clearance of apoptotic macrophages decreases neutrophil recruitment and invasive bacterial disease during pneumonia.
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影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
6.4
作者：
Ali, F;Lee, ME;Dockrell, DH
通讯作者：
Dockrell, DH
DOI：
10.1165/rcmb.2004-0108oc
发表时间：
2005-02-01
影响因子：
6.4
作者：
Jennings, JH;Linderman, DJ;Curtis, JL
通讯作者：
Curtis, JL
影响因子：
4.4
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM