|Year : 2017 | Volume
| Issue : 6 | Page : 260-263
Acute lung injury mechanism and therapy induced by paraquat poisoning
Xian-Li Liu1, Xiao-Ran Liu2, Chuan-Zhu Lu2
1 Hainan Medical University, 3 Xueyuan Rd, Longhua District, Haikou City, Hainan Province, 570000, China
2 Emergency Department, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570100, China
|Date of Submission||06-Sep-2017|
|Date of Decision||15-Sep-2017|
|Date of Acceptance||01-Oct-2017|
|Date of Web Publication||27-Dec-2017|
Emergency Department, The First Affiliated Hospital of Hainan Medical University, 31 Longhua Road, Haikou, Hainan
Emergency Department, The First Affiliated Hospital of Hainan Medical University, 31 Longhua Road, Haikou, Hainan
Source of Support: None, Conflict of Interest: None
Paraquat (PQ, methyl viologen) was widely used in agricultural production throughout the world in 1962 for its efficient herbicidal activity. PQ was also highly toxic drug. About 5 mL medicine including 20% paraquat was life-threatening that can cause poisoning. In 1966, some people died because of PQ poisoning. Most patients had acute respiratory distress syndrome after 2 wk, and 70% of them died due to the lack of effective detoxification drugs. Thus, it was particularly important to understand the pathogenesis of PQ poisoning and give some effective treatments. This article will review the toxicological mechanism and treatment on PQ poisoning of acute lung injury.
Keywords: Paraquat, Poisoning, Acute lung injury, Pulmonary fibrosis
|How to cite this article:|
Liu XL, Liu XR, Lu CZ. Acute lung injury mechanism and therapy induced by paraquat poisoning. J Acute Dis 2017;6:260-3
| 1. Toxicological mechanism of paraquat (PQ) poisoning of lung injury|| |
PQ concentration in the lung tissue reached its highest after 15 h of oral paraquat, which was 10-90 times the plasma concentration. This is due to the presence of polyamine transport system in the lungs that is located at epithelial cells of alveolar type I, alveolar type II cells and Clara cells. PQ, with similar structure to polyamines, is transported and utilized by those cells with effects on cellular energy metabolism, which is more pronounced under aerobic conditions. This ingestion has energy dependence and time dependence. PQ can cause cell damage by diffusing into pulmonary macrophages, interstitial cells and pulmonary vascular endothelial cells. Following will introduce some current theories related to toxicological mechanism of paraquat poisoning of lung injury.
1.1. Oxidative stress theory
Oxidative stress injury is currently the most in-depth study and also one of the main mechanisms of paraquat-induced lung injury. PQ exists as a bipyridyl cation in serum and is actively taken up by the lungs following by a redox reaction that produces a large amount of reactive oxygen species. After PQ getting into the lungs, a large amount of oxygen radicals and superoxide anion are produced under the action of nicotinamide adenine dinucleotide phosphate (NADPH) to form monovalent cation PQ, which then reacts with molecular oxygen to form divalent cations. It results in the existence of a large number of intracellular reactive oxygen species, which damages cell membrane of organelle in mitochondria and causes apoptosis; in the meantime, a large number of hydrogen peroxide generats and reacts with ferrous ions to form OH-, which damages alveolar epithelial and vascular endothelial cells, causing changes in membrane structure and function. The whole process consumes lots of NADPH, which affects intracellular tricarboxylic acid cycle process and inhibits ATP production.
1.2. Mitochondrial damage theory
PQ poisoning would produce lipid peroxide. Lipid peroxidation would increase mitochondrial membrane permeability and cause mitochondrial swelling, thus damaged the mitochondria leading to apoptosis of alveolar epithelial cells and pulmonary vascular endothelium cells. Calcium overload also plays an important role in PQ poisoning, which may be related to the abnormal opening of voltage-dependent calcium channel on mitochondrial membrane, leading to the deposition of phosphate in cytoplasm. This will aggravate the destruction of mitochondrial structure and function. Calcium overload may be one of the important mechanisms leading to acute lung injury (ALI) caused by mitochondrial injury of acute PQ poisoning.
1.3. Inflammatory mediators theory
In early stage of PQ poisoning, a large number of inflammatory cells and immune cell would infiltrate the poisoned place. PQ poisoning first to cause ALI, which had a large number of inflammatory cells gathering in the alveoli and mainly were alveolar macrophages cells, neutrophils etc. Alveolar macrophages cells could synthesize and release a large number of cytokines, inflammatory mediators, chemokines and proteases etc, leading to pejorative inflammation and injury of lung tissues. After PQ poisoning, inflammation occurred on the third day; percolate in the alveoli and hypertrophic fibroblasts began to accumulate on the seventh day, on which hypertrophic fibroblasts secreted collagen fibers and pulmonary fibrosis appeared; and normal alveolar structure was destroyed on day 14. Thus, inflammatory cells played an important role in the occurrence of PQ-induced ALI.
1.4. Interstitial cell proliferation theory
Song et al found that alveolar epithelial cells declined in earlier stage of PQ poisoning, but basal cells remained normal. Later, basal cells were also damaged, and interstitial cells proliferated into the alveoli leading to the formation of alveolar fibrosis. After these pathological changes, most of the alveolar wall remained intact. Alveolar fibrosis may result from epithelial cells damage and basal cell damage, as well as proliferation of interstitial cells.
1.5. Cytokines theory
PQ poisoning activated a large number of cytokines and caused lung injury. Expression of transforming growth factor-β (TGF-β ) was significantly increased in PQ poisoning-induced model of pulmonary fibrosis, and TGF-β was considered as the initiating hub of pulmonary fibrosis. TGF-β 1 was secreted by macrophages in the early stage of PQ poisoning, which can promote the transformation of fibroblasts into myofibroblasts; the latter interacted with pulmonary interstitium to promote the secretion and proliferation of mesenchymal stem cells; which can coordinate the role of other cytokines through paracrine effects, such as platelet-derived growth factor, insulin-like growth factor-1, interferon-γ etc, to mediate the early acute inflammatory reaction and advanced fibrosis. It can be found in lung and bronchoalveolar lavage fluid of PQ poisoning rat that monocyte inflammatory factor-2, interferon-γ , and tumor necrosis factor-were significantly higher than in control group.
1.6. DNA damage and apoptosis theory
PQ poisoning mechanism has been deep into the molecular and gene expression levels that DNA base changes and the destruction of the spiral bimolecular structure. PQ poisoning causes the production of a large number of oxygen free radicals, which is bad for DNA and can induce karyopyknosis and DNA strand breakage. PQ may induce cell damage by activating apoptosis signal regulating kinase-1.
| 2. Treatment methods|| |
Many researches were done on the treatment of PQ poisoning, but the effect was not ideal. The mortality is still very high. Three methods are recognized as the cornerstones of acute PQ poisoning treatment including early removing unabsorbed PQ residue, blood purification, and the application of immunosuppressive agents.
2.1. Toxic excretion
Some measures can be taken to prevent the continuous absorption of PQ including cleaning, gastric lavage, adsorption, and catharsis etc. PQ level in plasma was directly related to the prognosis of PQ poisoning patients. In addition to routine infusion and diuretic, the methods of hemodialysis, plasma perfusion and continuous venous filtration etc could promote PQ discharge in blood. As these technologies were in their infancy, their effects needs to be confirmed through further clinical validation.
2.2. Drug treatment
2.2.1. Application of hormones and immunosuppressive agents
Most scholars believed that the application of corticosteroids and cyclophosphamide in the treatment of PQ poisoning was a major breakthrough. Adreno cortico hormones had effects of anti-inflammatory, inhibiting neutrophil, accumulation and adhesion with lymphocyte in the lungs, as well as anti-lipid peroxidation etc. Cyclophosphamide played a role in all aspects of immunity of cells and humoral, with a strong anti-inflammatory effect.
2.2.2. Anti-oxidative therapy
Currently, most in medical profession thought that oxidative stress was one of the important mechanisms of PQ poisoning, and thus they recommended anti-oxidative therapy as a main treatment. Antioxidants such as edaravone, ambroxol, quercetin, acetylcysteine, vitamin C, etc, had influences on improvement of PQ poisoning. They can not significantly reduce the mortality rate, but had a certain effect on prognosis improvement and fibrosis inhibition.
2.3. Other treatments
There are some other treatments including symptomatic therapy, supportive treatment, oxygen therapy as well as lung and mesenchymal cells transplantation. Although no successful treatment case of lung transplantation had been reported yet, this method reported by Bertram et al could be considered at the critical moment and complete PQ removal in vivo may be achieved. Tsai et al reported that mesenchymal cells transplantation could improve the efficacy of PQ poisoning treatment, and they thought this treatment may be a promising one. In addition, adjuvant therapy of salicylate, ozone also had a certain effect on PQ poisoning, while further evidence-based clinical validation is needed
| 3. New ideas of treatment|| |
3.1. Amifostine (AMF)
AMF was a thiophosphate nucleophilic precursor. It functioned as the cytoprotective agents and anti-nuclear radiation protector that protected hematopoietic stem cells in bone from damages of chemotherapeutic agents, accelerated proliferation of stem cells, and improved noxiousness accumulation in cells. AMF was a radioprotectant for the treatment of adverse reactions to chemotherapy and radiotherapy, with effects of cleaning free radicals in tissue and anti-oxidant. In addition, AMF was similar to polyamines and PQ in molecular structure and could be used as a pseudo-polyamine to participate in chemical processes. AMF significantly prolonged survival time of mice with acute PQ poisoning, which may be able to combat the oxidation of PQ in vivo. Brandok et al also believed that AMF could theoretically be used as an antidote to PQ poisoning, but experiments had shown no effect of AMF on mortality and lung histopathology in PQ poisoning mice. Whild some demonstrated that repeated dosing of certain AMF could prevent lung tissue from PQ uptake and thus reduce the inflammatory and oxidative damages.
3.2. Stem cells
At present, how to apply stem cells to clinical diseases is the hotspot in the medical field. Bone mesenchymal stem cells (BMSCs) are adult stem cells that existe in bone marrow. They are deeply studied and have the potential of multidirectional differentiation and self-renewal, which are the ideal tools for tissue engineering and cell therapy. They can differentiate into many kinds of tissues under certain conditions, and they have been implanted into the treatment of various lung injuries in recent years. Some animal experiments showed that BMSCs had positive therapeutic effects on PQ-induced lung injury. BMSCs can differentiate into alveolar epithelial cells I and II, bronchial epithelial cells and fibroblasts,,, and can also promote lung tissue repair,. BMSCs transplantation could inhibit the inflammatory response of early poisoning. There were two methods related to BMSCs transplantation treatment on PQ poisoning-induced pulmonary fibrosis that firstly, BMSCs could migrate to damaged sites; and secondly, the transplantation of BMSCs could significantly reduce the content of TGF-β in damaged sites, thus inhibit the formation of pulmonary fibrosis. However, some studies had shown that there were no significant effects of BMSCs on pulmonary fibrosis, and may even worsen the situation. Yan et al showed that no significant change of pulmonary fibrosis was found in the BMSCs treatment group mice, and even myofibroblasts were generated deteriorating pulmonary fibrosis. Artificially controllable factors may have something to do with the paradoxical experiment results. BMSCs could be a new treatment for PQ poisoning, while the exact therapeutic effects were not clear yet. Further studies of BMSCs were required including studies about its potential acting mechanism, optimal infusion time, infusion doses and methods, as well as the safety.
| 4. Conclusion|| |
In summary, the mechanisms of PQ-induced human pathogenicity are complicated, of which oxidative stress theory is currently the most in-depth study and is also one of the main mechanisms of PQ-induced ALI. PQ poisoning must be treated in multiple ways. Most of poisoning patients die of pulmonary fibrosis. It can be believed that treatment on preventing the formation of pulmonary fibrosis will become the most important issue in the future.
Conflict of interest statement
The authors declare that they have no conflict of interest.
| References|| |
Chinese College Of Emergency Physicans. Expert consensus on diagnosis and treatment of acute paraquat poisoning. Chin J Crit Care Med
Xu L, Xu J, Wang Z. Molecular mechanisms of paraquat-induced acute lung injury: A current review. Drug Chem Toxicol
Rao R, Bhat R, Pathadka S, Chenji SK, Dsouza S. Golden hours in severe paraquat poisoning-the role of early hemoperfusion therapy. J Clin Diagn Res
Li GQ, Li YM, Wei LQ, Liu Y, Zhang YH. Comparison between kidney and continuous plasma perfusion for paraquat elimination. Am J Med
Gao HG, Cao Y. Research progree on pathogenesis of acute lung injure induced by acute paraquat poisoning. West China Med J
Afarnegan H, Shahraki A, Shahraki J. The hepatoprotective effects of aquatic extract of Levisticum officinale against paraquat hepatocyte toxicity. Pak J Pharm Sci
(Suppl 6): 2363-2368.
Wang HX, Yang LR, Lu JY, Peng SC. Study on mechanism and treatment of lung injury induced by paraquat poisoning. J Logist Univ PAPF (Med Sci
) 2014; 23
Wang RC, Stevens JB. Paraquat toxicity in vitro. I. Pulmonary alveolar macrophages. J Toxicol Environ Health
Hu X, Shen H, Wang Y, Zhao M. Liver X receptor agonist TO901317 attenuates paraquat-induced acute lung injury through inhibition of NF-κB and JNK/p38 MAPK signal pathways. Biomed Res Int
Milczarek R, Sokolowska E, Rybakowska I, Kaletha K, Klimek J. Paraquat inhibits progesterone synthesis in human placental mitochondria. Placenta
van der Merwe C, van Dyk HC, Engelbrecht L, van der Westhuizen FH, Kinnear C, Loos B, et al. Curcumin rescues a PINK1 knock down SH-SY5Y cellular model of Parkinson’s disease from mitochondrial dysfunction and cell death. Mol Neurobiol
Hu M, Wu W, Gong J, Li Y. The interventional effect of Xuebijing injection on expression of mitochondrial fusion protein 2 and the ultrastructure changes in lung tissues in rats with paraquat poisoning. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
Song HW, Yang C, Liu W, Liu XW, Liu Z, Gao F. Interleukin-17A plays the same role on mice acute lung injury respectively induced by lipopolysaccharide and paraquat. Inflammation
Chen Y, Nie YC, Luo YL, Lin F, Zheng YF, Cheng GH, et al. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol
Bernard K, Logsdon NJ, Benavides GA, Sanders Y, Zhang JH, Darley-Usmar VM, et al. Glutaminolysis is required for TGF-β 1-induced myofibroblast differentiation and activation. J Biol Chem
2017. doi: 10.1074/jbc.RA117.000444.
Sun B, Wang H, Zhang L, Yang X, Zhang M, Zhu X, et al. Role of interleukin 17 in TGF-β signaling-mediated renal interstitial fibrosis. Cytokine
2017. doi: 10.1016/j.cyto.2017.10.015.
Kanie S, Yokohira M, Yamakawa K, Nakano-Narusawa Y, Yoshida S, Hashimoto N, et al. Suppressive effects of the expectorant drug ambroxol hydrochloride on quartz-induced lunginflammation in F344 rats. J Toxicol Pathol
Rio MJ, Velez-Pardo C. Paraquat induces apoptosis in human lymphocytes: Protective and rescue of glucose, cannabinoids and insulin-like growth factor-1. Growth Factors
Niso-Santano M, Gonzalez-Polo RA. Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death:modulation by the Nrf2/Trx axis. Free Radic Biol Med
Li D, Zhang XW, Jiang XQ, Yin YJ, Fan Z, Sun CB, et al. Protective effects of thalidomide on pulmonary injuries in a rat model of paraquat intoxication. J Inflamm (Lond
) 2015; 12:
Yeh ST, Guo HR, Su YS, Lin HJ, Hou CC, Chen HM, et al. Protective effects of Nacetylcysteine treatment post-acute paraquat intoxication in rats and in human lung epithelial cells. Toxicology
Bertram A, Haenel SS, Hadem J, Hoeper MM, Gottlieb J, Warnecke G, et al. Tissue concentration of paraquat on day 32 after intoxication and failed bridge to transplantation by extracorporeal membrane oxygenation therapy. BMC Pharmacol Toxicol
Tsai HL. Amelioration of paraquat-induced pulmonary injury by mesenchymal stem cells. Cell Transplant
Dinis-Oliveira RJ, de Pinho PG, Ferreira AC, Silva AM, Afonso C, Bastos Mde L, et al. Reactivity of paraquat with sodium salicylate: Formation of stable complexes. Toxicology
Kaldirim U, Uysal B, Yuksel R, Macit E, Eyi YE, Toygar M, et al. Ozone therapy ameliorates paraquat-induced lung injury in rats. Exp Biol Med (Maywood
) 2014; 239
Guo HF, Wu LL, Feng AM, Zhao P, Jiang SF. Mechanism of amifostine combined with low dose cyclosporine in refractory immune thrombocytopenia. Chin J Biochem Pharm
Willd BK, Aks S, Maloney GE, Rhee J, Brand R, Sekosan M. The effect of amifostine, a cytoprotective agent, on paraquat toxicity in mice. J Med Toxicol
Johnke RM, Sattler JA, Allison RR. Radioprotective agents for radiation therapy: Future trends. Future Oncol
Lin ZM, Liang LB, Li JY, Liang RL, Liu S, Ren Y, et al. Preliminary study on amifostine against acute paraquat poisoning. J South Med Univ
Yang YC. Effect of amifostine on pulmonary uptake and lung injury in paraquat poisoning rats. Thesis. Anhui Medical University; 2012.
Nadkarni RR, Abed S, Draper JS. Stem cells in pulmonary disease and regeneration. Chest
2017. doi: 10.1016/j.chest.2017.07.021.
Stabler CT, Morrisey EE. Developmental pathways in lung regeneration. Cell Tissue Res
Wecht S, Rojas M. Mesenchymal stem cells in the treatment of chronic lung disease. Respirology
Chen F, Fine A. Stem cells in lung injury and repair. Am J Pathol
Horie S, Laffey JG. Recent insights: Mesenchymal stromal/stem cell therapy for acute respiratory distress syndrome. F1000Res
Yang H, Wen Y, Bin J, Hou-You Y, Yu-Tong W. Protection of bone marrow mesenchymal stem cells from acute lung injury induced by paraquat poisoning. Clin Toxicol (Phila
) 2011; 49
Zhao F, Li SQ, Di XY, Song LQ, Li ZK, Wu CG, Qi HW. Effects of bone marrow mesenchymal stem cells on transforming growth factor beta and monocyte chemoattractant protein-1 in lung injury rats. J Clin Rehabilit Tissue Eng Res
Yan X, Liu Y, Han Q, Jia M, Liao L, Qi M, Zhao RC. Injure microenviroment directly guides the differentiation of engrafted Flk-1(+) mesenchmal stem cell in lung. Exp Hematol
|This article has been cited by|
||Cardioprotective Effects of Atorvastatin Are Mediated Through PPAR? in Paraquat-Exposed Rats
| ||Mojtaba Malekinejad,Masoumeh Masoumi Verki,Mona Khoramjouy,Aylar Alenabi,Mahsa Hallaj-Salahipour,Hassan Malekinejad |
| ||Journal of Cardiovascular Pharmacology. 2019; 74(5): 400 |
|[Pubmed] | [DOI]|
||The Ameliorative Effects of Allopurinol on Paraquat-Induced Pulmonary Fibrosis in Rats
| ||Saeedeh Shariati,Mohammad Javad Khodayar,Aliasghar Hemmati,Mehdi Goudarzi,Milad Kiani,Anahita Rezaei |
| ||Pharmaceutical Sciences. 2019; 25(1): 11 |
|[Pubmed] | [DOI]|