Milk fat globule-epidermal growth factor-factor 8 attenuates neutrophil infiltration in acute lung injury via modulation of CXCR2.
Milk fat globule-epidermal growth factor-factor 8 attenuates neutrophil infiltration in acute lung injury via modulation of CXCR2.
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DOI：
10.4049/jimmunol.1200262
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发表时间：
2012-07-01
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Aziz M;Matsuda A;Yang WL;Jacob A;Wang P
过度的中性粒细胞浸润到肺是急性肺损伤（ALI）的一个标志。乳脂球- egf因子8 （MFG-E8）最初被确定为凋亡细胞的吞噬作用。随后的研究揭示了它的多种细胞功能。然而，MFG-E8是否能够调节中性粒细胞功能以减轻炎症尚不清楚。因此，我们旨在揭示MFG-E8在ALI期间调节肺中性粒细胞浸润中的作用。为了诱导ALI， C57BL/6J野生型（WT）和Mfge8−/−小鼠气管内注射LPS （5 mg/kg）。采用组织学方法观察肺组织损伤，并用血细胞计计数肺组织中性粒细胞。TUNEL法检测肺组织凋亡细胞，分光光度法检测caspase-3和MPO活性。流式细胞术检测CXCR2和GRK2在中性粒细胞中的表达。在LPS刺激下，Mfge8−/−小鼠表现出广泛的肺损伤，这是由于中性粒细胞的过度浸润和TNF-α、MIP-2和MPO的产生。与WT小鼠相比，mfge8−/−小鼠的肺中被捕获的凋亡细胞数量增加，这可能是由于凋亡细胞吞噬不足或通过激活caspase-3增加了凋亡的发生。使用MIP-2介导的趋化性的体外研究显示，通过增加CXCR2的表面暴露，Mfge8−/−小鼠的中性粒细胞迁移比WT小鼠高。重组小鼠（rm）MFG-E8通过上调GRK2和下调表面CXCR2表达来减少中性粒细胞迁移。相反，这些作用可以被抗αv整合素抗体阻断。这些研究清楚地表明MFG-E8在改善中性粒细胞浸润方面的重要性，并提示MFG-E8作为一种新的治疗ALI的潜力。
Excessive neutrophil infiltration to the lungs is a hallmark of acute lung injury (ALI). Milk fat globule-EGF factor 8 (MFG-E8) was originally identified for phagocytosis of apoptotic cells. Subsequent studies revealed its diverse cellular functions. However, whether MFG-E8 can regulate neutrophil function to alleviate inflammation is unknown. We therefore aimed to reveal MFG-E8 roles in regulating lung neutrophil infiltration during ALI. To induce ALI, C57BL/6J wild-type (WT) and Mfge8−/− mice were intra-tracheally injected with LPS (5 mg/kg). Lung tissue damage was assessed by histology and the neutrophils were counted by a hemacytometer. Apoptotic cells in lungs were determined by TUNEL, while caspase-3 and MPO activities were assessed spectrophotometrically. CXCR2 and GRK2 expressions in neutrophils were measured by flow cytometry. Following LPS challenge, Mfge8−/− mice exhibited extensive lung damage due to exaggerated infiltration of neutrophils and production of TNF-α, MIP-2 and MPO. Increased number of apoptotic cells was trapped into the lungs ofMfge8−/− mice than WT mice, which may be due to insufficient phagocytosis of apoptotic cells or increased occurrence of apoptosis through the activation of caspase-3. In vitro studies using MIP-2 mediated chemotaxis, revealed higher migration of neutrophils of Mfge8−/− mice than WT mice via increased surface exposures to CXCR2. Administration of recombinant mouse (rm)MFG-E8 reduces neutrophil migration through up-regulation of GRK2, and down-regulation of surface CXCR2 expression. Conversely, these effects could be blocked by anti-αv-integrin antibodies. These studies clearly indicate the importance of MFG-E8 in ameliorating neutrophil infiltration and suggest MFG-E8 as a novel therapeutic potential for ALI.
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影响因子：
3.7
作者：
Aziz M;Jacob A;Matsuda A;Wu R;Zhou M;Dong W;Yang WL;Wang P
通讯作者：
Wang P
影响因子：
8.8
作者：
Matsuda A;Wu R;Jacob A;Komura H;Zhou M;Wang Z;Aziz MM;Wang P
通讯作者：
Wang P
影响因子：
15.9
作者：
Jinushi, Masahisa;Nakazaki, Yukoh;Dranoff, Glenn
通讯作者：
Dranoff, Glenn
影响因子：
5.5
作者：
Boxio, R;Bossenmeyer-Pourié, C;Nüsse, O
通讯作者：
Nüsse, O
DOI：
10.1073/pnas.95.6.2985
发表时间：
1998-03-17
影响因子：
11.1
作者：
Aragay, AM;Mellado, M;Mayor, F
通讯作者：
Mayor, F