Paraquat-induced reactive oxygen species inhibit neutrophil apoptosis via a p38 MAPK/NF-κB-IL-6/TNF-α positive-feedback circuit.
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.
Emergency department, the 2nd affiliated hospital of Chongqing Medical University, Chongqing, China.
Xiaolong
X
Wang
Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Fuling
F
Luo
Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hengguang
H
Zhao
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006540:Herbicides / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010269:Paraquat / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006540:Herbicides; D053583:Interleukin-1beta; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D010269:Paraquat