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NOX4 Mediates <i>Pseudomonas aeruginosa</i>-Induced Nuclear Reactive Oxygen Species Generation and Chromatin Remodeling in Lung Epithelium

<i>Pseudomonas aeruginosa</i> (<i>PA</i>) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in <i>PA</i>-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC...

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Main Authors: Panfeng Fu (Author), Ramaswamy Ramchandran (Author), Tara Sudhadevi (Author), Prasanth P. K. Kumar (Author), Yashaswin Krishnan (Author), Yuru Liu (Author), Yutong Zhao (Author), Narasimham L. Parinandi (Author), Anantha Harijith (Author), Junichi Sadoshima (Author), Viswanathan Natarajan (Author)
Format: Book
Published: MDPI AG, 2021-03-01T00:00:00Z.
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Summary:<i>Pseudomonas aeruginosa</i> (<i>PA</i>) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in <i>PA</i>-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in <i>PA</i>-mediated chromatin remodeling and lung inflammation. Intratracheal administration of <i>PA</i> to Nox4<sup>flox/flox</sup> 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 <i>PA</i> stimulation increased the nuclear NOX4 expression and ROS production. Downregulation or inhibition of NOX4 and PKC δ attenuated the <i>PA</i>-induced nuclear ROS. <i>PA</i>-induced histone acetylation was attenuated by <i>Nox4</i>-specific siRNA, unlike <i>Nox2</i>. <i>PA</i> stimulation increased HDAC1/2 oxidation and reduced HDAC1/2 activity. The <i>PA</i>-induced oxidation of HDAC2 was attenuated by <i>N</i>-acetyl-L-cysteine and siRNA specific for <i>Pkc δ</i>, <i>Sphk2</i>, and <i>Nox4</i>. <i>PA</i> 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 <i>PA</i>-induced lung inflammatory injury via nuclear ROS generation, HDAC1/2 oxidation, and chromatin remodeling.
Item Description:10.3390/antiox10030477
2076-3921

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