Alpha-1-Antitrypsin Ameliorates Pristane Induced Diffuse Alveolar Hemorrhage in Mice
Alpha-1-Antitrypsin Ameliorates Pristane Induced Diffuse Alveolar Hemorrhage in Mice
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DOI：
10.3390/jcm8091341
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发表时间：
2019-09-01
影响因子：
3.9
通讯作者：
Song, Sihong
中科院分区：
文献类型：
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作者：
Elshikha, Ahmed S.;Abboud, Georges;Song, Sihong
弥漫性肺泡出血（DAH）是狼疮患者的致命并发症。腹腔注射降植烷可诱导B6小鼠DAH。由于人α-1-抗胰蛋白酶（hAAT）是一种抗炎和免疫调节蛋白，我们研究了hAAT对B6小鼠和hAAT转基因（hAAT-Tg）小鼠中降植烷诱导的DAH的保护作用。我们首先表明hAAT Tg表达降低了未处理小鼠中B细胞以及CD 4 + T细胞中TNF-α的产生。相反，调节性CD 4 + CD 25+和CD 4 + CD 25-IL-10+细胞的频率在hAAT-Tg中显著高于B6小鼠。这证实了即使在稳态下也观察到的hAAT的抗炎作用。在降植烷注射后一周，hAAT-Tg小鼠中腹膜Ly 6C（hi）炎性单核细胞和中性粒细胞的频率显著低于B6小鼠。重要的是，在hAAT-Tg小鼠中，降植烷诱导的DAH被完全阻止，这与抗炎性与促炎性骨髓细胞比率/平衡的调节有关。我们还表明，用hAAT治疗降低了B6小鼠中DAH的严重程度。这些结果首次表明hAAT具有治疗DAH的治疗潜力。
Diffuse alveolar hemorrhage (DAH) is a fatal complication in patients with lupus. DAH can be induced in B6 mice by an intraperitoneal injection of pristane. Since human alpha-1-antitrypsin (hAAT) is an anti-inflammatory and immuno-regulatory protein, we investigated the protective effect of hAAT against pristane-induced DAH in B6 mice and hAAT transgenic (hAAT-Tg) mice. We first showed that hAAT Tg expression lowers TNF-alpha production in B cells, as well as CD4+ T cells in untreated mice. Conversely, the frequency of regulatory CD4+CD25+ and CD4+CD25-IL-10+ cells was significantly higher in hAAT-Tg than in B6 mice. This confirmed the anti-inflammatory effect of hAAT that was observed even at steady state. One week after a pristane injection, the frequency of peritoneal Ly6C(hi) inflammatory monocytes and neutrophils in hAAT-Tg mice was significantly lower than that in B6 mice. Importantly, pristane-induced DAH was completely prevented in hAAT-Tg mice and this was associated with a modulation of anti- to pro-inflammatory myeloid cell ratio/balance. We also showed that treatment with hAAT decreased the severity of DAH in B6 mice. These results showed for the first time that hAAT has a therapeutic potential for the treatment of DAH.