Gastrin attenuates sepsis-induced myocardial dysfunction by down-regulation of TLR4 expression in macrophages.
Gastrin attenuates sepsis-induced myocardial dysfunction by down-regulation of TLR4 expression in macrophages.
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DOI：
10.1016/j.apsb.2023.06.012
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发表时间：
2023-09
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心肌功能障碍是脓毒症最严重的并发症。脓毒症诱发的心肌功能障碍（SMD）常与胃肠道功能障碍相关，但其病理生理意义尚不清楚。本研究发现SMD患者血浆胃泌素浓度高于无SMD者。在小鼠中，胃泌素受体，胆囊收缩素B受体（Cckbr）的敲低，加重脂多糖（LPS）诱导的心功能不全，增加心脏炎症，而静脉注射胃泌素改善SMD和心脏损伤。巨噬细胞浸润在SMD中起着重要作用，因为在LPS给药前48 h通过静脉注射氯膦酸盐脂质体消耗巨噬细胞，减轻了Cckbr缺陷小鼠中LPS诱导的心脏损伤。静脉注射过表达Cckbr的骨髓巨噬细胞（Bckbr）可减少LPS诱导的心肌功能障碍。此外，胃泌素处理通过过氧化物酶体增殖物激活受体α（PPAR-α）信号通路抑制Bcells中Toll样受体4（TLR 4）的表达。因此，我们的研究结果提供了深入了解胃泌素/CCKBR在SMD中的保护作用的机制，这可用于开发SMD的新治疗模式。Gastrin/CCKBR通过刺激PPAR-α的转录，抑制TLR 4的表达，进而抑制LPS/TLR 4/NF-κB轴的激活，减轻脓毒症引起的心肌功能障碍。
Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr-deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR-α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD. Gastrin/CCKBR inhibits the expression of TLR4 by stimulation of the transcription of PPAR-α, and thereby inhibits the activation of LPS/TLR4/NF-κB axis, and eventually attenuates sepsis-induced myocardial dysfunction.
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