Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1
Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1
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DOI：
10.1016/j.lfs.2016.10.010
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发表时间：
2016-12-01
期刊：
影响因子：
6.1
通讯作者：
Mizutani, Taro
中科院分区：
文献类型：
--
作者：
Matsuishi, Yujiro;Jesmin, Subrina;Mizutani, Taro
在与脓毒症相关的功能障碍和病理中，脓毒症诱导的急性肺损伤（ALI）的潜在分子机制尚不清楚。内皮素(ET)-1是一种有效的血管收缩剂和促炎肽，在脓毒症大鼠模型中参与了ALI的发病机制。在这里，我们研究了盐酸兰地洛尔，一种超短效β受体阻滞剂，是否通过调节ET-1系统在改善和减弱lps诱导的ALI中起关键作用。8周龄雄性Wistar大鼠分别给予生理盐水或脂多糖（LPS） 3小时（3小时），部分给予脂多糖的大鼠连续给予兰地洛尔3小时。LPS诱导ALI，包括循环和肺部tnf - α和IL-6水平，但[PaO2]明显降低。LPS还诱导肺ET-1和ET-A受体水平显著升高，但具有血管舒张作用的ET-B受体水平显著降低。此外，LPS可上调肺中HIF-1 α的表达。最后，用脂多糖给药的大鼠用兰地洛尔治疗3小时，改善和预防ALI，使肺ET-1和ET-A受体水平正常化。兰地洛尔在脓毒症早期（阶段）也诱导肺组织ET-B受体显著下调。然而，兰地洛尔治疗对脓毒症期间血浆和肺组织中上调的炎症介质（tnf - α、IL-6）没有影响，并且肺HIF-1 α的表达也在兰地洛尔治疗后保持不变。总的来说，这些数据使我们得出结论，兰地洛尔可能通过肺ET系统改善败血症诱导的ALI。(C) 2016年由Elsevier Inc.出版。
Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3 h) and some of the LPS-administered rats were continuously treated with landiolol for 3 h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-alpha and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1 alpha. Finally, the treatment of LPS-administered rats with landiolol for 3 h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-alpha, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1 alpha also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system. (C) 2016 Published by Elsevier Inc.