Oncotarget

Research Papers:

Novel mechanisms for crotonaldehyde-induced lung edema

Yue Li, Jianjun Chang, Yong Cui, Runzhen Zhao, Yan Ding, Yapeng Hou, Zhiyu Zhou, Hong-Long Ji and Hongguang Nie _

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Oncotarget. 2017; 8:83509-83522. https://doi.org/10.18632/oncotarget.17840

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Abstract

Yue Li1,*, Jianjun Chang1,*, Yong Cui2, Runzhen Zhao3, Yan Ding1, Yapeng Hou1, Zhiyu Zhou1, Hong-Long Ji3,4 and Hongguang Nie1

1Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang 110122, Liaoning, China

2Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China

3Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA

4Texas Lung Injury Institute, University of Texas Health Northeast, Tyler, Texas 75708, USA

*These authors have contributed equally to this work

Correspondence to:

Hongguang Nie, email: [email protected]

Hong-Long Ji, email: [email protected]

Keywords: epithelial sodium channels, crotonaldehyde, lung injury, alveolar fluid clearance, reactive oxygen species

Received: March 17, 2017    Accepted: April 25, 2017    Published: May 12, 2017

ABSTRACT

Background: Crotonaldehyde is a highly noxious α,β-unsaturated aldehyde in cigarette smoke that causes edematous acute lung injury.

Objective: To understand how crotonaldehyde impairs lung function, we examined its effects on human epithelial sodium channels (ENaC), which are major contributors to alveolar fluid clearance.

Methods: We studied alveolar fluid clearance in C57 mice and ENaC activity was examined in H441 cells. Expression of α- and γ-ENaC was measured at protein and mRNA levels by western blot and real-time PCR, respectively. Intracellular ROS levels were detected by the dichlorofluorescein assay. Heterologous αβγ-ENaC activity was observed in an oocyte model.

Results: Our results showed that crotonaldehyde reduced transalveolar fluid clearance in mice. Furthermore, ENaC activity in H441 cells was inhibited by crotonaldehyde dose-dependently. Expression of α- and γ-subunits of ENaC was decreased at the protein and mRNA level in H441 cells exposed to crotonaldehyde, which was probably mediated by the increase in phosphorylated extracellular signal-regulated protein kinases 1 and 2. ROS levels increased time-dependently in cells exposed to crotonaldehyde. Heterologous αβγ-ENaC activity was rapidly eliminated by crotonaldehyde.

Conclusion: Our findings suggest that crotonaldehyde causes edematous acute lung injury by eliminating ENaC activity at least partly via facilitating the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 signal molecules. Long-term exposure may decrease the expression of ENaC subunits and damage the cell membrane integrity, as well as increase the levels of cellular ROS products.


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