3.5 Effect of edaravone on pulmonary fibrosis and survival rate in patients with PQ poisoning
All deaths occurred due to overdoses of PQ, complicated with respiratory failure and pulmonary fibrosis. This study showed that edaravone could delay the occurrence of pulmonary fibrosis and increase the survival time of patients at 7 and 14 days after poisoning. However, the 1-month follow-up found that edaravone did not reduce pulmonary fibrosis and did not increase the survival rate of the patients.
PQ is a widely used, also known as herbicide, is a nonselective, fast acting herbicide. Patients with large doses of PQ died in the short term due to acute lung injury, liver failure, and kidney failure. The main target organs of PQ injury are the lungs. The pathological changes follow this sequence: alveolar type I, type II epithelial cells were destroyed, a large number of neutrophils infiltrated the alveolar septum to form pneumonia, the normal alveolar structure was destroyed, resulting in gas exchange barriers, and the patients died early due to intractable hypoxemia.[9,10] Currently, the research on the mechanism of multiple organ dysfunction caused by PQ poisoning is mainly involved in calcium overload, inflammation overexpression, free radical and abnormal gene expression, in which excessive inflammatory reactions and oxidative stress are particularly important.[11–14] Animal and clinical studies have confirmed that PQ can promote the expression and release of NF-κB, IL-6, and TNF-α and thus cause damage to the lungs.[14,15] Additionally, PQ produces large amounts of oxidative free radicals, induces lipid peroxides, and directly damages the lungs and other tissues and organs. Edaravone was originally developed as a neuroprotective drug. It is a powerful antioxidant that has a very strong free radical scavenging ability and can reduce inflammatory factors including IL-6, TGF-β, and TNF-α.[16,17] This study found that PQ can induce the upregulation of IL-6, IL-10, and TNF-α in patients with PQ poisoning, but edaravone can inhibit the upregulation of these inflammatory factors (IL-6, IL-10, and TNF-α), which shows that edaravone has a good anti-inflammatory effect in the treatment of PQ poisoning (Table 5).
PQ poisoning can lead to a significant increase in reactive oxygen species, which has been identified as one of the important causes of acute tubular necrosis and acute kidney injury. Approximately 51% of intoxication patients will suffer from acute kidney injury and approximately 37% of patients will eventually die of renal failure or multiple organ failure.[18–20] Except for mild PQ poisoning, the most serious injury to the respiratory system, liver, and kidneys is caused by inhalation or intake of PQ from the digestive tract. Additionally, the main cause of death is the damage and failure of the cardiovascular system and other multiple systems in the middle and severe late stages of PQ poisoning.[18–20] At present, a large number of studies have confirmed that the changes in the levels of MDA and SOD reflect the ability of anti-lipid peroxidation and scavenging oxygen free radicals.[21,22] In this study, we found that edaravone could significantly inhibit the serum MDA content in patients with PQ poisoning, and increase the content of serum SOD. All of these revealed severe anti-lipid peroxidation damage and the ability to scavenge oxygen free radicals. In addition, this study showed that edaravone could significantly inhibit liver and kidney injury and cardiovascular complications in the middle and later stages of PQ poisoning. The possible reason is that edaravone is a new type of free radical scavenger, which inhibits the formation of free radicals and the lipid peroxidation chain reaction of the cell membrane, and effectively inhibits the destruction of proteins and nucleic acids. At the same time, a highly permeable edaravone can effectively inhibit the damage in tissue cells and the vascular endothelium, minimizing injury to tissues and preserving organ function. This allows it to function in protecting organs.
Lung injury is the most important consequence of PQ poisoning, because the alveolar type II cells have the characteristics of active uptake and accumulation of PQ, therefore the lung damage is the most obvious and serious sign of PQ poisoning. Lung injury is characterized by acute chemical pulmonary interstitial lesions and the rapid development of pulmonary fibrosis, resulting in intractable hypoxemia and respiratory failure, which eventually leads to multiple organ damage or failure.[9,19] Currently, there is no specific method for clinical treatment of PQ poisoning. It is mainly treated through gastric lavage, catharsis, hemoperfusion, hemodialysis clearance of poisons, steroid impact therapy against organ damage and symptomatic support therapy, and so on. However, the effect is not satisfactory, and thus, the mortality of PQ poisoning is very high, up to 50% to 80%.[1,23] Most studies have shown that edaravone can inhibit pulmonary fibrosis in animal experiments.[24,25] However, our results suggest that edaravone can delay pulmonary fibrosis, but does not inhibit the development of pulmonary fibrosis. Edaravone significantly delayed pulmonary fibrosis and increased the patients’ survival time at seventh and fourteenth days of treatment, but at the 1-month follow-up, edaravone did not reduce the incidence of pulmonary fibrosis or increase the patients’ survival rate. Edaravone can delay the production and development of pulmonary fibrosis, increase the survival time of the patients, and provide a possible follow-up treatment, but does not reverse the development of pulmonary fibrosis.
In conclusion, we found that edaravone had a strong protective effect on liver and kidney damage but had no significant improvement in the digestive tract and on the respiratory damage induced by PQ poisoning. Edaravone did not reduce pulmonary fibrosis in patients with PQ poisoning but did delay the generation and development of pulmonary fibrosis. Edaravone prolonged the survival time of patients, but had no significant effect on the survival rate. Certainly, because of the lack of sample size in this study, the design is not a multicenter randomized controlled study, more clinical and basic experimental studies are needed to further confirm our findings.
Conceptualization: Ren Yi, Sun Zhaorui, Nie Shinan.
Data curation: Ren Yi, Nie Shinan.
Formal analysis: Ren Yi, Yang Zhizhou, Zhang Wei, Chen Xin, Nie Shinan.
Funding acquisition: Ren Yi, Yang Zhizhou, Sun Zhaorui, Zhang Wei, Chen Xin, Nie Shinan.
Investigation: Ren Yi, Yang Zhizhou, Sun Zhaorui, Nie Shinan.
Methodology: Ren Yi, Yang Zhizhou, Sun Zhaorui, Zhang Wei, Chen Xin, Nie Shinan.
Project administration: Ren Yi, Yang Zhizhou, Sun Zhaorui, Nie Shinan.
Resources: Ren Yi, Yang Zhizhou, Zhang Wei, Chen Xin, Nie Shinan.
Software: Ren Yi, Yang Zhizhou, Sun Zhaorui, Zhang Wei, Chen Xin, Nie Shinan.
Supervision: Ren Yi, Yang Zhizhou, Sun Zhaorui, Chen Xin, Nie Shinan.
Validation: Ren Yi, Yang Zhizhou, Sun Zhaorui, Zhang Wei, Chen Xin, Nie Shinan.
Visualization: Ren Yi, Zhang Wei, Nie Shinan.
Writing – original draft: Ren Yi, Sun Zhaorui, Nie Shinan.
Writing – review and editing: Ren Yi, Nie Shinan.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
edaravone; inflammation; oxidative stress; paraquat poisoning; pulmonary fibrosis