Chen Xiao-Yue, Feng Po-Hao, Han Chia-Li, Jheng Yu-Teng, Wu Chih-Da, Chou Hsiu-Chu, Chen Yi-Ying, Wu Sheng-Ming, Lee Kang-Yun, Kuo Han-Pin, Chung Kian Fan, Hsiao Ta-Chih, Chen Kuan-Yuan, Ho Shu-Chuan, Chang Ta-Yuan, Chuang Hsiao-Chi
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Environ Pollut. 2021 Jun 1;278:116863. doi: 10.1016/j.envpol.2021.116863. Epub 2021 Mar 9.
Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = -0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution.
α-胰蛋白酶抑制剂重链4（ITIH4）是一种II型急性期蛋白；然而，暴露于空气污染后肺部ITIH4的作用仍不清楚。在本研究中，我们调查了ITIH4在肺部对空气污染的反应中的作用。测定了47名健康人类受试者以及全身暴露于空气污染的Sprague-Dawley大鼠支气管肺泡灌洗液（BAL）中的ITIH4表达，并研究了柴油废气颗粒（DEP）诱导的肺泡上皮A549细胞中潜在的抗凋亡和基质稳定途径以及ITIH4基因敲低情况。我们发现，人类BAL中PM的四分位距（IQR）增加与ITIH4降低2.673 ng/mL、8-异前列腺素增加1.104 pg/mL以及白细胞介素（IL）-6增加6.918 pg/mL相关。在大鼠中，暴露于PM和气态污染物后，肺部8-异前列腺素、IL-6和p53增加，沉默信息调节因子1（Sirt1）减少，BAL、肺部和血清中的ITIH4减少。肺裂解物中的ITIH4水平与BAL样本中的水平相关（r = 0.377，p < 0.01），而BAL中的ITIH4水平与IL-6水平相关（r = -0.420，p < 0.01）。DEP以剂量依赖的方式显著降低肺泡上皮A549细胞中的ITIH4表达。DEP暴露和ITIH4基因敲低后，观察到Sirt1减少，磷酸化细胞外信号调节激酶（p-ERK）和半胱天冬酶-3增加。总之，空气污染降低了肺部ITIH4的表达，这与肺泡上皮细胞衰老和凋亡相关。ITIH4可能是调节空气污染暴露后肺泡细胞破坏及其抑制的关键蛋白。
