HIF-1α promotes paraquat induced acute lung injury and implicates a role NF-κB and Rac2 activity.

Abstract

Paraquat (PQ) is a bipyridine herbicide and oral exposure is the main way of PQ exposure with a very high mortality. At present, it is believed that large number of oxygen free radicals are generated and cause lipid peroxidation of tissue and organ cell membranes after PQ is absorbed. PQ exposure could cause multiple organ dysfunction, among which acute lung injury is the most common and most serious. However, its specific mechanism is still unclear. In this study, the C57BL/6J mouse (alveolar epithelial cell-specific knockout HIF-1α) model of acute lung injury (40 mg/kg PQ) at several time pointes and a model of acute type II alveolar epithelial cell (A549, 800 μM PQ) injury constructed. The oxidative stress (ROS, MDA) and inflammatory response (IL-1β, IL-6, TNF-α) were significantly inhibited in the alveolar epithelial cell-specific knockout of HIF-1α mice and siRNA technology to inhibit HIF-1α in alveolar epithelial cells. Further proteomic analysis showed that the expression of Rac2 protein, which is closely related to oxidative stress, was significantly increased after PQ exposure. And the inhibition of Rac2 expression in vitro significantly alleviated PQ-induced oxidative stress and inflammatory response. The expression of Rac2 protein was regulated by HIF-1α. The above suggests that HIF-1α may promote oxidative stress and inflammatory response in alveolar epithelial cells by regulating the expression of Rac2, and then participate in the promotion of PQ exposure-induced acute lung injury.

• Authors: Yong Zhu, Xiaoxiao Meng, Wenyu Yang, Jinfeng Wang, Jiaxiang Zhang, Rui Tian, Ruilan Wang, Qi Su, Wei Jin
• Journal: Toxicology (Toxicology) Vol. 483 Pg. 153388 (01 01 2023) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 36462643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• NF-kappa B
• Paraquat
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• rac2 GTP-binding protein
• rac GTP-Binding Proteins

Topics

• Animals
• Mice
• Acute Lung Injury (chemically induced, metabolism)
• Lung (metabolism)
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Paraquat (toxicity)
• Proteomics
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects, metabolism)
• rac GTP-Binding Proteins (metabolism)