Inhibition of myeloid differentiation factor 2 by baicalein protects against acute lung injury
Inhibition of myeloid differentiation factor 2 by baicalein protects against acute lung injury
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DOI：
10.1016/j.phymed.2019.152997
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发表时间：
2019-10-01
期刊：
影响因子：
7.9
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Hongjin;Zhang, Yali;Liang, Guang
研究背景：急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是一种以严重低氧血症性呼吸衰竭为特征的炎症性组织损伤。没有治疗方法能够预防/逆转这些患者的可怕病理后遗症。证据将炎性肺损伤与免疫信号复合物TLR 4-MD 2（Toll样受体-髓样分化因子2）的不受控制的激活联系起来。黄芩素（Baicalein）是一种天然黄酮类化合物，具有较强的抗炎作用，但其抗炎机制尚不清楚。使用常规方法分析血液、BALF、肺和肝组织。结果：黄芩素是一种MD 2抑制剂，能直接与MD 2结合，有效抑制TLR 4-MD 2的活化以及随后的MAPK和NF-κ B信号通路。受抑制的MD 2阻止了炎性组织损伤的发展并提高了存活率。从MD 2（-/-）小鼠获得的数据证实了MD 2在ALI中的炎性损伤中的重要性，所述MD 2（-/-）小鼠没有发展特征性LPS诱导的肺组织损伤。结论：黄芩素作为一种直接选择性的MD 2抑制剂，可抑制TLR 4-MD 2信号通路的早期上游通路，有望成为治疗ALI/ARDS的有效药物。
Background: ALI/ARDS is characterized by severe hypoxemic respiratory failure attributed to inflammatory tissue injury. There are no treatment modalities able to prevent/reverse the dire pathological sequelae in these patients. Evidence links the inflammatory lung injury to uncontrolled activation of the immune signaling complex, TLR4-MD2 (Toll-like receptor-myeloid differentiation factor 2). Baicalein, a natural flavonoid, is reported to have robust anti-inflammatory properties, but its inhibition mechanism remains unclear.Hypothesis/Purpose: This study investigated the protective mechanisms of baicalein on ALI/ARDS.Methods: We used two experimental mouse models of LPS-induced ALI, pulmonary infection model (intratracheal LPS), and systemic infection model (intravenous LPS). Blood, BALF, lung and liver tissues were analyzed using routine methods. In vitro studies using peritoneal mouse macrophages or recombinant proteins were designed to elucidate inhibition mechanisms of baicalein.Results: Our critical new findings revealed that Baicalein was an MD2 inhibitor, directly bound to MD2, effectively suppressing TLR4-MD2 activation and the subsequent MAPK and NF-kappa B signaling. The inhibited MD2 prevented development of inflammatory tissue injury and improved survival. The importance of MD2 in the inflammatory injury in ALI was corroborated by data obtained from MD2(-/-) mice, which did not develop the characteristic LPS-induced lung tissue damage. Thus, the findings indicated that MD2 was critical for development of ALI, functioning as an early upstream signal driving the progression of inflammatory injury.Conclusion: Baicalein, as a direct and selective MD2 inhibitor, inhibited the early upstream TLR4-MD2 signaling and is a promising therapeutic agent for the treatment of ALI/ARDS.