Metformin Regulates Alveolar Macrophage Polarization to Protect Against Acute Lung Injury in Rats Caused by Paraquat Poisoning.

This study explored the role of metformin (MET) in regulating the polarization of alveolar macrophages to protect against acute lung injury (ALI) in rats caused by paraquat (PQ) poisoning. The in vivo studies showed that the 35 mg/kg dose of MET increased the survival rate of rats, alleviated pathological damages to the lungs and their systemic inflammation, promoted the reduction of the pro-inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels, and increased the anti-inflammatory factor IL-10 levels in the rat serum. At the same time, the MET intervention decreased the expression of M1 macrophage marker iNOS in the lungs of the PQ-poisoned rats while increasing the M2 macrophage marker, Arg1, expression. In vitro, the concentration of MET > 10 mmol/L affected NR8383 viability adversely and was concentration-dependent; however, no adverse impact on NR8383 viability was observed at MET ≤ 10 mmol/L concentration, resisting the reducing effect of PQ on NR8383 vitality. The PQ-induced NR8383 model with MET intervention showed significantly reduced secretions of IL-6 and TNF-α in NR8383, and lowered expressions of M1 macrophage markers iNOS and CD86. Additionally, MET increased IL-10 secretion and the M2 macrophage markers, Arg1 and Mrcl, expressions. Therefore, we speculate that MET could regulate alveolar macrophage polarization to protect against PQ-poisoning caused ALI.

Successful Treatment of Severe Toxic Hepatitis and Encephalopathy Without Respiratory Failure Caused by Paraquat Intoxication.

Lung damage is a characteristic feature of paraquat intoxication; most deaths resulting from ingesting paraquat are due to progressive respiratory failure. Liver failure caused by paraquat intoxication is rare. A case of orally ingested paraquat intoxication is reported in which serious liver injury and toxic encephalopathy were observed, but little lung damage was found. The principal systemic symptom was severe liver injury, characterized by cholestasis, that gradually became aggravated. In addition to standard treatment, aggressive treatment through liver protection and cholestasis was administered. Finally, liver function returned to normal and central nervous system symptoms were controlled. The patient was successfully discharged. This case suggests that the hepatotoxicity of paraquat intoxication is possibly characterized by cholestasis, and the treatment of cholestasis promotes recovery of severe hepatocyte damage.

Paraquat promotes acute lung injury in rats by regulating alveolar macrophage polarization through glycolysis.

The present study investigates whether paraquat (PQ) regulates polarization of alveolar macrophages through glycolysis and promotes the occurrence of acute lung injury in rats. In vivo, the PQ intraperitoneal injection was used to construct a model of acute lung injury in rats. In vitro, the study measured the effect of different concentrations of PQ on the viability of the alveolar macrophages, and explored the polarization and glycolysis metabolism of alveolar macrophages at different time points after PQ intervention. Compared with the normal control (NC) group, the lung pathological damage in rats increased gradually after PQ poisoning, reaching a significant degree at 48 h after poisoning. The PQ-poisoned rat serum showed increased expressions of interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), and M1 macrophage marker, iNOS, while the expression of interleukin-10 (IL-10) and M2 macrophage marker, Arg1, decreased. The toxic effect of PQ on alveolar macrophages was dose- and time-dependent. Compared with the NC group, IL-6 and TNF-α in the cell supernatant gradually increased after PQ intervention, while the IL-10 content gradually decreased. The PQ intervention in alveolar macrophages increased the expression of intracellular glycolysis rate-limiting enzyme pyruvate kinase isozymes M1/M2 (PKM1/M2), lactate, lactate/pyruvate ratio, and the polarization of alveolar macrophage towards M1. Inhibition of cellular glycolysis significantly reduced the PQ-induced alveolar macrophage polarization to M1 type. Thus, PQ induced increased polarization of lung macrophages toward M1 and decreased polarization toward M2, promoting acute lung injury. Therefore, it can be concluded that PQ regulates the polarization of alveolar macrophages through glycolysis.

Comparison of Pancreatic Damage in Rats for Two Methods of Paraquat Administration.

It is noted that elevated serum amylase levels suggesting pancreatic damage has an association with prognosis in PQ patients. This study aimed to determine whether PQ can cause pancreatic damage. The two conventional models (intragastric infusion (iG) and intraperitoneal injection (iP)) may exhibit different effects on the pancreas depending on whether or not they pass through the digestive tract. In this study, the rats were divided into four groups: the intragastric infusion group (PQ-iG, n = 45), intraperitoneal injection group (PQ-iP, n = 53), normal control group 1 (NC-iG, n = 6) and normal control group 2 (NC-iP, n = 6). Pancreatic damage was compared between groups using serum amylase activity assay, hematoxylin and eosin (H&E) staining, TUNEL assay, and transmission electron microscopy (TEM). Serum amylase levels in group PQ-iG were significantly higher than in group PQ-iP (p < 0.05). Examination of the H&E sections showed damage to the pancreas. Both experimental groups were displayed inflammatory infiltration within 9 h of PQ treatment. After 9 h, patchy necrosis was observed in group PQ-iP, when inflammatory infiltration was still the dominant pathology. Necrosis appeared and gradually worsened in group PQ-iG, in which necrosis was the dominant pathology. The TUNEL assay showed significantly higher numbers of apoptotic cells in the pancreas of PQ-groups than in the control NC- groups (p < 0.05). TEM showed expansive endoplasmic reticulum lumens and mitochondria swelling in the pancreas of the PQ-groups. It is concluded that both methods of modeling could cause pancreatic damage and the type and degree of damage would change over time. Note that pancreatic damage in group PQ-iG was more severe than that in group PQ-iP. Therefore, clinical practitioners should pay close attention to pancreatic damage caused by PQ, especially when the route of PQ administration was oral.

A novel simple risk model to predict the prognosis of patients with paraquat poisoning.

To identify risk factors and develop a simple model to predict early prognosis of acute paraquat (PQ) poisoning patients, we performed a retrospective cohort study of acute PQ poisoning patients (n = 1199). Patients (n = 913) with PQ poisoning from 2011 to 2018 were randomly divided into training (n = 609) and test (n = 304) samples. Another two independent cohorts were used as validation samples for a different time (n = 207) and site (n = 79). Risk factors were identified using a logistic model with Markov Chain Monte Carlo (MCMC) simulation and further evaluated using a latent class analysis. The prediction score was developed based on the training sample and was evaluated using the testing and validation samples. Eight factors, including age, ingestion volume, creatine kinase-MB [CK-MB], platelet [PLT], white blood cell [WBC], neutrophil counts [N], gamma-glutamyl transferase [GGT], and serum creatinine [Cr] were identified as independent risk indicators of in-hospital death events. The risk model had C statistics of 0.895 (95% CI 0.855-0.928), 0.891 (95% CI 0.848-0.932), and 0.829 (95% CI 0.455-1.000), and predictive ranges of 4.6-98.2%, 2.3-94.9%, and 0-12.5% for the test, validation_time, and validation_site samples, respectively. In the training sample, the risk model classified 18.4%, 59.9%, and 21.7% of patients into the high-, average-, and low-risk groups, with corresponding probabilities of 0.985, 0.365, and 0.03 for in-hospital death events. We developed and evaluated a simple risk model to predict the prognosis of patients with acute PQ poisoning. This risk scoring system could be helpful for identifying high-risk patients and reducing mortality due to PQ poisoning.

Octreotide alleviates pancreatic damage caused by paraquat in rats by reducing inflammatory responses and oxidative stress.

This study explores the efficacy and mechanism by which octreotide (OCT) alleviates paraquat (PQ)-induced pancreatic injury. Twenty-four adult male rats were randomly divided into three groups: the normal control (NC), PQ poisoning, and OCT treatment groups. The PQ-induced pancreatic injury rat model was established by administering PQ (120 mg/kg). Treatment group rats received OCT (8 µg/kg body weight) every 8 h by subcutaneous injection, 1 h after PQ administration. Rats were euthanized 24 h after PQ injection. Serum amylase, lipase, tumor necrosis factor-α, and interleukin-6 levels were markedly increased in the PQ group versus the NC group. In pancreatic tissue, PQ poisoning drastically induced necrosis and increased inflammatory cytokine and oxidative stress marker levels. Compared with the PQ group, OCT reduced pancreatic damage and histological scores, serum amylase, lipase, and inflammatory cytokine levels, as well as oxidative stress. OCT demonstrates protective effects against PQ-induced pancreatic damage through anti-inflammatory and antioxidant actions.

Immunosuppressive drugs to reduce the mortality rate in patients with moderate to severe paraquat poisoning: A Meta-analysis.

The benefits and adverse effects of immunosuppressive drugs (ISDs) in patients with paraquat (PQ) poisoning have not been thoroughly assessed. This meta-analysis study aims to evaluate the effect of ISDs in patients with moderate to severe PQ poisoning. We searched PubMed, Embase, Cochrane Library, Ovid Medline, CNKI and Wanfang Data from inception to January 2019. The Mantel-Haenszel method with a random-effects model was used to calculate the pooled relative risks (RRs) and 95% Confidence Intervals (CIs) as described by DerSimonian and Laird. An L'Abbé plot was drawn to explore the relationship between the degree of poisoning and mortality. Four randomized controlled trials, two prospective and seven retrospective studies were identified. ISDs were significantly associated with reduced mortality (RR 0.76; 95% CI, 0.58-0.99) and the incidence rate of multiple-organ dysfunction syndrome (MODS) (RR 0.63; 95% CI, 0.48-0.83) in patients with moderate to severe PQ poisoning. They were not associated with an increased incidence rate of hepatitis and reduced incidence rate of acute renal failure and hypoxia. The L'Abbé plot results showed a slight increase in mortality rate in the ISD group with increased mortality in the placebo group. This indicates a possible advantage of ISDs in most of the patients with severe PQ poisoning. These findings suggest that ISDs may reduce the mortality and incidence rate of MODS in moderate to severe PQ poisoning patients, and severe PQ poisoning patients might benefit more from ISDs.

Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction.

BACKGROUND: With its high morbidity and mortality, acute myocardial infarction (AMI) places a major burden on society and on individual patients. Correct, early correct diagnosis is crucial to the management of AMI. METHODS: In this study, the expression of circulating miR-486 and miR-150 was investigated in AMI patients and the two miRNAs were evaluated as potential biomarkers for AMI. Plasma samples from 110 patients with AMI (65 patients with ST-segment elevation myocardial infarction (STEMI) and 45 patients with non-ST-segment elevation myocardial infarction (NSTEMI)) and 110 healthy adults were collected. Circulating levels of miR-486 and miR-150 were detected using quantitative real-time PCR in plasma samples. RESULTS: Results showed that the levels of miR-486 and miR-150 were significantly higher in AMI patients than in healthy controls. Receiver operating characteristic (ROC) curve analyses indicated that the two plasma miRNAs were of significant diagnostic value for AMI, especially NSTEMI. The combined ROC analysis revealed an AUC value of 0.771 in discriminating AMI patients from healthy controls and an AUC value of 0.845 in discriminating NSTEMI patients from healthy controls. CONCLUSION: Results indicated that the levels of circulating miR-486 and miR-150 are associated with AMI. They may be novel and powerful biomarkers for AMI, especially for NSTEMI.