炎症体
半胱氨酸蛋白酶1
肺动脉高压
炎症
半胱氨酸蛋白酶
细胞凋亡
吡喃结构域
缺氧(环境)
下调和上调
半胱氨酸蛋白酶3
癌症研究
白细胞介素
医学
细胞因子
免疫学
化学
内科学
程序性细胞死亡
生物化学
有机化学
氧气
基因
作者
Wuwei Rong,Chenchen Liu,Xiaoming Li,Naifu Wan,Lijiang Wei,Wentong Zhu,Peiyuan Bai,Ming Li,Yangjing Ou,Li Fang,Lingxia Wang,Xuanhui Wu,Jianling Liu,Mingyan Xing,Xiaoming Zhao,Han Liu,Haibing Zhang,Ankang Lyu
标识
DOI:10.1161/atvbaha.121.317168
摘要
Macrophages are involved in the pathogenesis of pulmonary arterial hypertension (PAH). Caspase-8, an apical component of cell death pathways, is significantly upregulated in macrophages of PAH animal models. However, its role in PAH remains unclear. Caspase-8 plays a critical role in regulating inflammatory responses via inflammasome activation, cell death, and cytokine induction. This study investigated the mechanism of regulation of IL-1β (interleukin 1β) activation in macrophages by caspase-8.A hypoxia + SU5416-induced PAH mouse model and monocrotaline-induced rat model of PAH were constructed and the role of caspase-8 was analyzed.Caspase-8 and cleaved-caspase-8 were significantly upregulated in the lung tissues of SU5416 and hypoxia-treated PAH mice and monocrotaline-treated rats. Pharmacological inhibition of caspase-8 alleviated PAH compared with wild-type mice, observed as a significant reduction in right ventricular systolic pressure, ratio of right ventricular wall to left ventricular wall plus ventricular septum, pulmonary vascular media thickness, and pulmonary vascular muscularization; caspase-8 ablated mice also showed significant remission. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cellss is closely associated with activation of the NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome and the IL-1β signaling pathway. Although caspase-8 did not affect extracellular matrix synthesis, it promoted inflammatory cell infiltration and pulmonary arterial smooth muscle cell proliferation via NLRP3/IL-1β activation during the development stage of PAH.Taken together, our study suggests that macrophage-derived IL-1β via caspase-8-dependent canonical inflammasome is required for macrophages to play a pathogenic role in pulmonary perivascular inflammation.
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