Fu Panfeng, Ramchandran Ramaswamy, Sudhadevi Tara, Kumar Prasanth P K, Krishnan Yashaswin, Liu Yuru, Zhao Yutong, Parinandi Narasimham L, Harijith Anantha, Sadoshima Junichi, Natarajan Viswanathan
Departments of Pharmacology & Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
Antioxidants (Basel). 2021 Mar 17;10(3):477. doi: 10.3390/antiox10030477.
() infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in -mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in -mediated chromatin remodeling and lung inflammation. Intratracheal administration of to Nox4 mice for 24 h caused lung inflammatory injury; however, epithelial cell-deleted Nox4 mice exhibited reduced lung inflammatory injury, oxidative stress, secretion of pro-inflammatory cytokines, and decreased histone acetylation. In LEpCs, NOX4 was localized both in the cytoplasmic and nuclear fractions, and stimulation increased the nuclear NOX4 expression and ROS production. Downregulation or inhibition of NOX4 and PKC δ attenuated the -induced nuclear ROS. -induced histone acetylation was attenuated by -specific siRNA, unlike . stimulation increased HDAC1/2 oxidation and reduced HDAC1/2 activity. The -induced oxidation of HDAC2 was attenuated by -acetyl-L-cysteine and siRNA specific for , , and . stimulated RAC1 activation in the nucleus and enhanced the association between HDAC2 and RAC1, p-PKC δ, and NOX4 in LEpCs. Our results revealed a critical role for the alveolar epithelial NOX4 in mediating -induced lung inflammatory injury via nuclear ROS generation, HDAC1/2 oxidation, and chromatin remodeling.
（）感染会增加活性氧（ROS），并且此前我们已证明烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶衍生的ROS在介导的肺部炎症和损伤中发挥作用。在此，我们展示了肺上皮细胞（LEpC）中的NOX4在介导的染色质重塑和肺部炎症中的作用。对Nox4小鼠气管内给予 24 小时会导致肺部炎性损伤；然而，上皮细胞缺失 Nox4 的小鼠肺部炎性损伤、氧化应激、促炎细胞因子分泌减少，且组蛋白乙酰化降低。在 LEpCs 中，NOX4 定位于细胞质和细胞核部分，并且刺激会增加细胞核中 NOX4 的表达和 ROS 产生。NOX4 和蛋白激酶 Cδ（PKCδ）的下调或抑制会减弱诱导的细胞核 ROS。与 不同，诱导的组蛋白乙酰化会被特异性小干扰 RNA（siRNA）减弱。刺激会增加组蛋白去乙酰化酶 1/2（HDAC1/2）的氧化并降低 HDAC1/2 的活性。诱导的 HDAC2 氧化会被 -乙酰半胱氨酸以及针对 、 和 的特异性 siRNA 减弱。刺激细胞核中的RAC1 激活，并增强 LEpCs 中 HDAC2 与 RAC1、磷酸化 PKCδ 和 NOX4 之间的关联。我们的结果揭示了肺泡上皮 NOX4 在通过细胞核 ROS 生成、HDAC1/2 氧化和染色质重塑介导诱导的肺部炎性损伤中起关键作用。
