Pulmonary Surfactant Protein A Protects Lung Epithelium from Cytotoxicity of Human β-Defensin 3
Pulmonary Surfactant Protein A Protects Lung Epithelium from Cytotoxicity of Human β-Defensin 3
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DOI：
10.1074/jbc.m111.308056
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发表时间：
2012-04-27
影响因子：
4.8
通讯作者：
Kuroki, Yoshio
中科院分区：
文献类型：
--
作者：
Saito, Atsushi;Ariki, Shigeru;Kuroki, Yoshio
防御素是先天免疫系统中消灭传染性微生物的重要分子。它们在较高浓度下还表现出针对宿主细胞的细胞毒性。人们对宿主保护自身细胞免受防御素细胞毒性的机制知之甚少。我们发现，人β-防御素 3 (hBD3) 对肺上皮细胞的细胞毒性会被肺表面活性蛋白 A (SP-A) 剂量依赖性减弱，SP-A 是一种参与宿主防御和肺部炎症反应调节的集合素。 SP-A 和 hBD3 之间的直接相互作用可能是降低这种细胞毒性的重要因素，因为上皮细胞与 SP-A 预孵育不会影响细胞毒性。与体外分析一致，与WT小鼠相比，SP-A(-/-)小鼠气管内施用hBD3导致更严重的组织损伤。这些数据表明 SP-A 可以保护肺上皮免受 hBD3 引起的组织损伤。此外，我们发现SP-A的功能区位于Tyr(161)-Lys(201)内。与该区域相对应的合成肽（暂称为SP-A Y161-G200）也以剂量依赖性方式抑制hBD3的细胞毒性。 SP-A Y161-G200 是一种候选治疗试剂，可预防炎症期间的组织损伤。
Defensins are important molecules in the innate immune system that eliminate infectious microbes. They also exhibit cytotoxicity against host cells in higher concentrations. The mechanisms by which hosts protect their own cells from cytotoxicity of defensins have been poorly understood. We found that the cytotoxicity of human beta-defensin 3 (hBD3) against lung epithelial cells was dose-dependently attenuated by pulmonary surfactant protein A (SP-A), a collectin implicated in host defense and regulation of inflammatory responses in the lung. The direct interaction between SP-A and hBD3 may be an important factor in decreasing this cytotoxicity because preincubation of epithelial cells with SP-A did not affect the cytotoxicity. Consistent with in vitro analysis, intratracheal administration of hBD3 to SP-A(-/-) mice resulted in more severe tissue damage compared with that in WT mice. These data indicate that SP-A protects lung epithelium from tissue injury caused by hBD3. Furthermore, we found that the functional region of SP-A lies within Tyr(161)-Lys(201). Synthetic peptide corresponding to this region, tentatively called SP-A Y161-G200, also inhibited cytotoxicity of hBD3 in a dose-dependent manner. The SP-A Y161-G200 is a candidate as a therapeutic reagent that prevents tissue injury during inflammation.