Zhou Tao, Jia Di, Han Jiahui, Xu Ce, You Xiaohong, Ge Xin
Department of Pharmacy, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China.
Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China.
Folia Histochem Cytobiol. 2023;61(1):56-67. doi: 10.5603/FHC.a2023.0006. Epub 2023 Mar 7.
Acute pulmonary embolism (APE) is a clinical syndrome of pulmonary circulation disorder caused by obstruction of the pulmonary artery or its branches. Histone deacetylase 6 (HDAC6) has been reported to play an important role in lung-related diseases. However, the functional role of HDAC6 in APE remains unclear.
Male Sprague Dawley rats were used. The APE model was constructed by inserting an intravenous cannula into the right femoral vein and injecting Sephadex G-50 microspheres (12 mg/kg; 300 μm in diameter). After 1 h, the control and APE rats were intraperitoneally injected with tubastatin A (TubA) (40 mg/kg, an inhibitor of HDAC6) and sampled at 24 h after modeling. H&E staining, arterial blood gas analysis, and wet/dry (W/D) weight ratio were used to evaluate the histopathological changes and pulmonary function in APE rats. ELISA, Western blot, and immunohistochemistry were used to explore the potential mechanism of HDAC6-mediated inflammation in APE.
The results indicated that HDAC6 expression was significantly increased in lungs of APE rats. TubA treatment in vivo decreased HDAC6 expression in lung tissues. HDAC6 inhibition alleviated histopathological damage and pulmonary dysfunction, as evidenced by decreased PaO2/FiO2 ratio and W/D weight ratio in APE rats. Furthermore, HDAC6 inhibition alleviated APE-induced inflammatory response. Specifically, APE rats exhibited increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-18, however, this increase was reversed by HDAC6 inhibition. Meanwhile, the activation of the NLRP3 inflammasome was also observed in lungs of APE rats, while HDAC6 inhibition blocked this activation. Mechanically, we demonstrated that HDAC6 inhibition blocked the activation of the protein kinase B (AKT)/extracellular signal-regulated protein kinase (ERK) signaling pathway, a classic pathway promoting inflammation.
These findings demonstrate that the inhibition of HDAC6 may alleviate lung dysfunction and pathological injury resulting from APE by blocking the AKT/ERK signaling pathway, providing new theoretical fundamentals for APE therapy.
急性肺栓塞（APE）是一种由肺动脉或其分支阻塞引起的肺循环障碍临床综合征。据报道，组蛋白去乙酰化酶6（HDAC6）在肺部相关疾病中起重要作用。然而，HDAC6在APE中的功能作用仍不清楚。
使用雄性Sprague Dawley大鼠。通过将静脉插管插入右股静脉并注射葡聚糖凝胶G-50微球（12mg/kg；直径300μm）构建APE模型。1小时后，将对照大鼠和APE大鼠腹腔注射tubastatin A（TubA）（40mg/kg，HDAC6抑制剂），并在建模后24小时取样。采用苏木精-伊红（H&E）染色、动脉血气分析和湿/干（W/D）重量比来评估APE大鼠的组织病理学变化和肺功能。采用酶联免疫吸附测定（ELISA）、蛋白质印迹法和免疫组织化学法探讨HDAC6介导的APE炎症潜在机制。
结果表明，APE大鼠肺组织中HDAC6表达显著增加。体内给予TubA治疗可降低肺组织中HDAC6表达。HDAC6抑制减轻了组织病理学损伤和肺功能障碍，APE大鼠的动脉血氧分压/吸入氧分数值（PaO2/FiO2）比值和W/D重量比降低证明了这一点。此外，HDAC6抑制减轻了APE诱导的炎症反应。具体而言，APE大鼠促炎细胞因子生成增加，包括肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6和IL-18，然而，HDAC6抑制可逆转这种增加。同时，在APE大鼠肺组织中也观察到NLRP3炎性小体的激活，而HDAC6抑制可阻断这种激活。从机制上来说，我们证明HDAC6抑制阻断了蛋白激酶B（AKT）/细胞外信号调节蛋白激酶（ERK）信号通路的激活，这是一条促进炎症的经典信号通路。
这些研究结果表明，抑制HDAC6可能通过阻断AKT/ERK信号通路减轻APE导致的肺功能障碍和病理损伤，为APE治疗提供了新的理论基础。
