Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Shock. 2019 Mar;51(3):389-400. doi: 10.1097/SHK.0000000000001144.
Acute lung injury (ALI) is a severe outcome of sepsis. Alveolar macrophages (AMs) play key roles in defense, resolution in ALI. The polarization of AMs is dependent on micro environmental stimuli and might influence the progression of ALI. Gainesville Tokushima scientists (GTS)-21, a selective α7 nicotinic acetylcholine receptor agonist of the cholinergic anti-inflammatory pathway (CAP), has recently been established to be promising in the treatment of ALI. However, the molecular mechanism underlying the GTS-21-mediated suppression of inflammatory responses has been explored only partially. In this study, we examined the relation between GTS-21 and AM polarization in ALI.
The adoptive transfer of M1 (classically activated) and M2 (alternatively activated)-polarized AMs was performed to AM-depleted ALI mice, along with the administration of GTS-21 in a murine model of lipopolysaccharide (LPS)-induced ALI and in isolated AMs that had been stimulated by LPS in vitro.
The adoptive transfer of M1-polarized AMs aggravated the inflammatory response in the lung in contrast to the adoptive transfer of M2-polarized AMs. GTS-21 protected the lung from the effect of LPS, preventing injury and decreasing the number of AMs, AM-related pro-inflammatory cytokine levels, high mobility group box 1 expression levels in AMs. In addition, GTS-21 significantly diminished the number of M1-polarized AM and increased the number of M2-polarized AM, by flow cytometry, RT-PCR, enzyme-linked immunosorbent assay, and the Arg1 and iNOS activity assays.
The GTS-21 substantially ameliorates LPS-induced ALI. This protection is predominantly associated with the inhibition of pulmonary AM M1 polarization and alteration in AM function.
急性肺损伤（ALI）是脓毒症的严重后果。肺泡巨噬细胞（AMs）在防御和 ALI 中的解决中起着关键作用。AMs 的极化取决于微环境刺激，并可能影响 ALI 的进展。Gainesville Tokushima 科学家（GTS）-21，一种胆碱能抗炎途径（CAP）的选择性α7 烟碱乙酰胆碱受体激动剂，最近已被证明在治疗 ALI 方面很有前途。然而，GTS-21 介导的抑制炎症反应的分子机制仅部分得到了探索。在这项研究中，我们研究了 GTS-21 与 ALI 中 AM 极化之间的关系。
采用经典激活（M1）和交替激活（M2）极化的 AM 过继转移方法，在脂多糖（LPS）诱导的 ALI 小鼠模型中以及在 LPS 体外刺激的分离 AM 中，给予 GTS-21 治疗。
与 M2 极化的 AM 过继转移相比，M1 极化的 AM 过继转移加重了肺部的炎症反应。GTS-21 可保护肺部免受 LPS 的影响，防止损伤并减少 AM 数量、AM 相关促炎细胞因子水平、AM 中高迁移率族蛋白 1 表达水平。此外，通过流式细胞术、RT-PCR、酶联免疫吸附试验和 Arg1 和 iNOS 活性测定，GTS-21 显著减少了 M1 极化 AM 的数量，增加了 M2 极化 AM 的数量。
GTS-21 可显著改善 LPS 诱导的 ALI。这种保护主要与抑制肺 AM M1 极化和改变 AM 功能有关。
