Paraquat-induced reactive oxygen species inhibit neutrophil apoptosis via a p38 MAPK/NF-κB-IL-6/TNF-α positive-feedback circuit.

Xiaolong Wang,Hengguang Zhao,Fuling Luo,Jinah Choi

doi:10.1371/journal.pone.0093837

Abstract

Paraquat (PQ), a widely used herbicide and potent reactive oxygen species (ROS) inducer, can injure multiple tissues and organs, especially the lung. However, the underlying mechanism is still poorly understood. According to previous reports, neutrophil aggregation and excessive ROS production might play pivotal pathogenetic roles. In the present study, we found that PQ could prolong neutrophil lifespan and induce ROS generation in a concentration-independent manner. Activated nuclear factor-κB (NF-κB), p38 mitogen-activated kinase (p38 MAPK), and myeloid cell leukemia sequence 1 (Mcl-1) but not Akt signaling pathways were involved in this process, as well as increasing levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β. Furthermore, the proinflammatory mediators IL-6 and TNF-α could in turn promote ROS generation, creating a vicious cycle. The existence of such a feedback loop is supported by our finding that neutrophil apoptosis is attenuated by PQ in a concentration-independent manner and could partially explain the clinical dilemma why oxygen therapy will exacerbate PQ induced tissue injury.

Highlights

The nonselective contact herbicide paraquat (PQ) is a strong pneumotoxicant; it accumulates in the lung through a polyamine uptake system and can induce redox cycling, leading to oxidative stress-related damage [1,2]
We further investigated the effects of PQ on neutrophil apoptosis and found that it prolonged neutrophil lifespan in a concentrationindependent manner, and this delay of neutrophil apoptosis might, at least partly, through its effects on a positive feedback circuit involving p38 MAPK, nuclear factor-kB (NF-kB), IL-6, and tumor necrosis factor-a (TNF-a)
We found that stimulation with 1 mM PQ did not affect neutrophil survival, but 5, 50, or 100 mM PQ significantly delayed neutrophil apoptosis at all assessed time points (6, 12, 18 and 24 h after treatment) (Fig. 1)

Summary

Introduction

The nonselective contact herbicide paraquat (PQ) is a strong pneumotoxicant; it accumulates in the lung through a polyamine uptake system and can induce redox cycling, leading to oxidative stress-related damage [1,2]. Evidence has shown that reactive oxygen species (ROS) occupy a central role in PQ-induced acute lung injury (ALI). As intrinsic signal transduction molecules, ROS are important components in the complex modulation of neutrophil apoptosis [4,5]. Control of neutrophil apoptosis is essential to rapidly resolve inflammatory reactions [7]. Recent studies have shown that apoptosis contributes to ALI pathogenesis, and neutrophil apoptosis in particular exacerbates the condition [8,9,10,11]

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Results

Conclusion