Monocyte Chemoattractant Protein-1 Released from Alveolar Macrophages Mediates the Systemic Inflammation of Acute Alveolar Hypoxia
Monocyte Chemoattractant Protein-1 Released from Alveolar Macrophages Mediates the Systemic Inflammation of Acute Alveolar Hypoxia
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DOI：
10.1165/rcmb.2010-0264oc
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发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Gonzalez, Norberto C.
中科院分区：
文献类型：
--
作者：
Chao, Jie;Donham, Paula;Gonzalez, Norberto C.
肺泡缺氧在大鼠体内引起迅速的全身炎症。一些证据表明，炎症不是由全身组织低氧分压(PO(2))引起的，而是由低氧肺泡巨噬细胞释放到循环中的一种介质引起的。该介体激活组织肥大细胞以启动炎症。低氧肺泡巨噬细胞迅速释放单核细胞趋化蛋白-1/趋化因子配体2(MCP-1/CCL2)。本研究探讨单核细胞趋化蛋白-1(MCP-1)是否是肺泡缺氧全身性炎症的介质。在大鼠、肺泡巨噬细胞和腹膜肥大细胞上的实验得出了几个结果。(1)肺泡低氧(10%O(2)呼吸，60min)可使清醒正常大鼠血浆MCP-1浓度迅速升高(5分钟)，而肺泡巨噬细胞耗竭大鼠则无明显变化。(2)当肥大细胞浸泡在缺氧正常大鼠的血浆中而不浸泡在肺泡巨噬细胞耗竭大鼠的血浆中时，肥大细胞发生脱颗粒。(3)常氧大鼠血浆和肺泡巨噬细胞培养上清液中加入MCP-1后，浸泡的肥大细胞呈浓度依赖性脱颗粒。(4)正常大鼠肠系膜局部应用MCP-1可复制肺泡缺氧性炎症反应。(5)CCR2b受体拮抗剂RS-102895可预防正常大鼠肺泡低氧所致的肠系膜炎症。更多的数据表明，一种在肺泡巨噬细胞中结构性产生并存在于常氧体液中的辅因子是MCP-1在生物相关浓度下激活肥大细胞所必需的。我们认为，肺泡巨噬细胞携带的单核细胞趋化蛋白-1在肺泡低氧全身炎症的启动中起关键作用。
Alveolar hypoxia produces rapid systemic inflammation in rats. Several lines of evidence suggest that the inflammation is not initiated by low systemic tissue partial pressure of oxygen (PO(2)) but by a mediator released into the circulation by hypoxic alveolar macrophages. The mediator activates tissue mast cells to initiate inflammation. Monocyte chemoattractant protein-1/Chemokine (C-C motif) ligand 2 (MCP-1/CCL2) is rapidly released by hypoxic alveolar macrophages. This study investigated whether MCP-1 is the mediator of the systemic inflammation of alveolar hypoxia. Experiments in rats and in alveolar macrophages and peritoneal mast cells led to several results. (1) Alveolar hypoxia (10% O(2) breathing, 60 minutes) produced a rapid (5-minute) increase in plasma MCP-1 concentrations in conscious intact rats but not in alveolar macrophage-depleted rats. (2) Degranulation occurred when mast cells were immersed in the plasma of hypoxic intact rats but not in the plasma of alveolar macrophage-depleted rats. (3) MCP-1 added to normoxic rat plasma and the supernatant of normoxic alveolar macrophages produced a concentration-dependent degranulation of immersed mast cells. (4) MCP-1 applied to the mesentery of normoxic intact rats replicated the inflammation of alveolar hypoxia. (5) The CCR2b receptor antagonist RS-102895 prevented the mesenteric inflammation of alveolar hypoxia in intact rats. Additional data suggest that a cofactor constitutively generated in alveolar macrophages and present in normoxic body fluids is necessary for MCP-1 to activate mast cells at biologically relevant concentrations. We conclude that alveolar macrophage-borne MCP-1 is a key agent in the initiation of the systemic inflammation of alveolar hypoxia.