Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

The role of Kupffer cell activation in immune liver damage induced by trichloroethylene associated with the IFN-γ/STAT1 signaling pathway.

Trichloroethylene (TCE) is a metal detergent commonly used in industry that can enter the human body through the respiratory tract and skin, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and multiple organ damage, including liver failure. However, the pathogenesis of liver injury remains unclear. Kupffer cells (KCs) are important tissue macrophages in the body because the polarization of KCs plays a crucial role in immune-mediated liver injury. However, the mechanism of KCs polarization in TCE-induced immune liver injury has not been thoroughly elucidated. In this study, we investigated the effect of TCE-induced KCs polarization on liver function and signal transduction pathways using the TCE sensitization model developed by our group. BALB/c mouse skin was exposed to TCE for sensitization, and an increase in the expression of M1 macrophage-specific markers (CD16/CD32, iNOS), M1 macrophage-specific cytokines IL-1ß, and IFN-γ, P-JAK-1 and P-STAT1 levels were also found to be dramatically increased. When using low doses of gadolinium trichloride (GdCl3), the expression of these proteins and mRNA was significantly reduced. This phenomenon indicates that GdCl3 blocks TCE-induced polarization of KCs and suggests that the IFN-γ/STAT1 signaling pathway may be involved in the polarization process of KCs. These findings clarify the relationship between the polarization of KCs and immune liver injury and highlight the importance of further study of immune-mediated liver injury in TCE-sensitized mice.

TNF-α/TNFR1 regulates the polarization of Kupffer cells to mediate trichloroethylene-induced liver injury.

We have previously shown trichloroethylene (TCE) induced immune liver injury, and TNF-α/TNFR1 pathway as a probably mechanism underlying the immune damage, but the pathogenic mechanism is still unclear. The study aims to investigate whether TNF-α and its receptors regulate Kupffer cell polarization and downstream inflammation signaling pathways during TCE sensitization, to clarify the mechanism of TCE-mediated immune liver injury. 6-8 weeks old SPF BALB/c female mice were used to establish a TCE sensitization model. We found that in the TCE sensitization positive group, liver injury was aggravated, Kupffer cells activated and polarized to M1 type. The expression of M1 Kupffer cell marker proteins CD11c and CD16/32 increased in the TCE positive group, so did TNF-α and TNFR1 in liver. The expression of P-IKK protein, PP65 protein and P-STAT3 protein increased in the TCE sensitization positive group, and the downstream inflammatory factors IL-1ß and IL-6 also increased in the TCE sensitization positive group. After using the TNFR1 inhibitor R7050, we found that M1 Kupffer cell polarization, TNF-α expression, signal pathway expression and inflammatory factors IL-1ß and IL-6 expression declined, and the liver damage relieved. Briefly, the use of R7050 to inhibit TNF-α/TNFR1 changing the polarization of liver M1 Kupffer cell, thereby inhibiting the activation of related downstream signaling pathways and reducing the secretion of inflammatory factors. TNF-α/TNFR1 regulates the polarization of M1 Kupffer cells inflammatory play an important role in liver immune damage.

Identification of Key Genes for Hepatitis Delta Virus-Related Hepatocellular Carcinoma by Bioinformatics Analysis.

BACKGROUND: It has been proposed that hepatitis delta virus (HDV) induces hepatic carcinogenesis by distinct molecular events compared with hepatocellular carcinoma (HCC) that is commonly induced by other hepatitis viruses. This study aimed to explore the underlying mechanism by identifying the key genes for HDV-HCC using bioinformatics analysis. METHODS: The GSE107170 dataset was downloaded and the differentially expressed genes (DEGs) were obtained by the online tool GEO2R. Gene otology (GO) functional analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using R packages. The protein-protein interaction (PPI) network was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Hub genes were selected by Cytoscape software according to degree algorithm. The hub genes were further validated in terms of expression and survival analysis based on public databases. RESULTS: A total of 93 commonly upregulated genes and 36 commonly downregulated genes were found. The top 5 upregulated hub genes were TFRC, ACTR2, ARPC1A, ARPC3, and ARPC2. The top 5 downregulated hub genes were CTNNB1, CCND1, CDKN1B, CDK4, and CDKN1A. In the validation analysis, the expressions of ARPC1A, ARPC3, and CDK4 were promoted in general liver cancer samples. Higher expressions of ARPC2 and CDK4 and lower expressions of CDKN1A, CCND1, and CDKN1B were associated with worse prognosis in general HCC patients. CONCLUSION: The present study identifies a series of key genes that may be involved in the carcinogenesis of HDV-HCC and used as prognostic factors.

Cauliflower-shaped lesions on a young woman's vulva.

A 20-year-old young woman with cauliflower-shaped lesions on her vulva was misdiagnosed as condyloma acuminatum. Further evaluation revealed positive serological tests for syphilis. On histological examination, and numerous plasma cells were seen to infiltrate the dermis heavily. The cauliflower-shaped lesions on vulva completely disappeared after benzathine penicillin treatment. Cauliflower-shaped lesions are a rare manifestation of secondary syphilis.

Kupffer cell inactivation ameliorates immune liver injury via TNF-α/TNFR1 signal pathway in trichloroethylene sensitized mice.

METHODS: 36 female BALB/c mice were selected and randomly divided the mice into four groups. We established a BALB/c mouse model of TCE sensitization and pretreatment with GdCl3 (40 mg/kg) by intraperitoneal injection during the during the 17th and 19th days. RESULTS: We found F4/80, the marker of Kupffer cell, was increased in TCE positive group. GdCl3 treatment successfully blocked the activation of Kupffer cell. TNF-α was increased significantly in liver of TCE sensitized mice and decreased significantly when low-dose GdCl3 was used. We found TNF receptor 1 (TNFR1) was increased significantly and GdCl3 treatment resumed the expression of TNFR1 to normal level, as well as the F4/80, TNF-α and TNFR1 mRNA. We also found both caspase-8 and caspase-3 increased in TCE positive group and decreased in TCE + GdCl3 positive group. The number of apoptotic cells in TCE sensitized mice increased by TUNEL staining, and GdCl3 treatment alleviated this increase. Some cells showed edema and inflammatory cell aggregation in liver of TCE positive group, while in the TCE + GdCl3 positive group, the cytoplasm became loose and vacuole-like degeneration occurred. CONCLUSION: Our study unveils cross-talk between Kupffer cell activation and TNFR1 which mediate apoptosis in liver of TCE sensitized mice.

Kupffer cell depletion attenuates IL-6/STAT3 mediates hepatocyte apoptosis in immunological liver injury of trichloroethylene sensitized mice.

Trichloroethylene (TCE) induced TCE hypersensitivity syndrome which makes immune injuries in multi-system. The multiple organ damage included skin, liver, kidney and so on. The main manifestations of liver injuries were apoptosis and edema of hepatocytes. In our previous research, we found the activation of Kupffer cells (KCs) which increased IL-6 can aggravate liver cell apoptosis in TCE sensitized mice. However, the mechanism of IL-6 in liver damages induced by TCE was not clear. This study explored the function of IL-6/STAT3 signal pathway on the TCE induced apoptosis of liver cell. We established a TCE sensitized BALB/c mouse model with a KCs inhibitor GdCl3, we found that the expressions of ALT and AST in TCE sensitization positive mice were higher than other mice, and the expressions of apoptosis-related proteins were up-regulated in TCE sensitization positive mice, GdCl3 could alleviate this process. Meanwhile, GdCl3 could significantly decrease the expressions of IL-6/STAT3 proteins. All in all, the activation of KCs can increase the expression of IL-6, IL-6R and phosphorylate STAT3, induces hepatocyte apoptosis, and participates in immunity damage of liver which induced by TCE.

Dietary Fat Intake and the Risk of Skin Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

We conducted a meta-analysis to evaluate the association between fat intake and the risk of three major types of skin cancer including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). A comprehensive search of PubMed and EMBASE was performed to identify all relevant observational studies published up to December 1, 2018. Specific odds ratio (OR) or relative risk (RR) estimates for the highest versus the lowest intake of dietary fat and 95% confidence intervals (CI) from the included studies were pooled using random effect model. Three prospective cohort studies (175,675 participants and 30,915 BCC cases, 4,106 SCC cases and 1,638 CMM cases) and nine case-control studies (328 BCC cases, 493 SCC cases, 1,547 CMM cases and 2,660 controls) were identified. The pooled results indicated that dietary consumption of total fat and saturated fat were not associated with three major types of skin cancer. High consumption of monounsaturated fat was significantly associated with a decreased risk of BCC (RR: 0.90, 95% CI: 0.85-0.96) and high level of polyunsaturated fat intake was potentially positively associated with SCC (RR: 1.19, 95% CI: 1.06-1.33). Our findings should be confirmed by further evidence from well-designed and large-scale prospective cohort studies.

Inflammatory kidney injury in trichloroethylene hypersensitivity syndrome mice: Possible role of C3a receptor in the accumulation of Th17 phenotype.

Trichloroethylene (TCE) is a common organic solvent which can cause TCE hypersensitivity syndrome (THS) in exposure workers. THS is an adverse skin disorder with severe inflammatory kidney damage. Complement C3a receptor (C3aR) acts as a specific receptor for the key complement cleavage product C3a and involves multiple inflammatory responses, but the role of C3aR in TCE induced kidney inflammatory injury remains unknown. In this study, BALB/c mouse model of skin sensitization induced by TCE was set up in the presence or absence of C3aR antagonist (C3aRA). Kidney pathology and renal function, expression of inflammatory mediators and C3aR, changes in Th17 cell numbers, and activation of signal transducer and activator of transcription 3 (STAT3) in the kidney were examined. TCE sensitization produced histopathological and functional damage to the kidney, accompanied by increased levels of interleukin (IL-) 1ß, IL-6, and IL-23. Local accumulation of Th17 cells and enhanced phosphorylation of STAT3 were also seen in the impaired kidney in TCE sensitization-positive mice. C3aR was mainly located in the impaired glomerulus and upregulated in TCE sensitization-positive mice. C3aRA pretreatment alleviated the structural and functional kidney damage and the inflammatory cytokine and Th17 responses by TCE sensitization, and specifically reduced the phosphorylation of STAT3. Together, our results demonstrate that C3aR signaling promotes the inflammatory responses and regulates the accumulation of Th17 phenotype via phosphorylation of STAT3 in TCE sensitization induced inflammatory kidney damage. C3aR may serve as a potential therapeutic target in TCE sensitization mediated kidney injury.

Terminal complement complex C5b-9 reduced megalin and cubilin-mediated tubule proteins uptake in a mouse model of trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.

Complement regulatory protein CD59a plays a protective role in immune liver injury of trichloroethylene-sensitized BALB/c mice.

Trichloroethylene (TCE) is a major occupational and environmental chemical compound which causes occupational dermatitis medicamentosa-like of TCE with severe liver damage. Our previous studies showed that complement activation was a newly recognized mechanism for TCE-induced liver damage. The objective of this study was to explore the role of the key complement regulatory protein, CD59a, in TCE-induced immune liver injury. We firstly evaluated the changes of CD59a expression in liver tissue and then investigated if the changes were associated with membrane attack complex (MAC) formation, nuclear factor kappa B (NF-κB) activation and liver damage in BALB/c mice model of TCE-induced skin sensitization in the absence or presence of soluble recombinant rat CD59-Cys. The results showed that low expression of CD59a accompanied by MAC deposition in the liver of TCE-sensitized BALB/c mice, which was consistent in time. In addition, activation of NF-κB pathway, upregulation of inflammatory cytokine and liver damage also occured. Additional experiment showed that recombinant rat sCD59-Cys alleviated inflammation and liver damage in TCE-sensitized BALB/c mice. Moreover, recombinant rat sCD59-Cys reduced MAC formation and inhibited NF-κB activation measured by P-IκBα and nuclear NF-κB p65 in the liver of TCE-sensitized BALB/c mice. In conclusion, recombinant rat sCD59-Cys plays a protective role in immune liver injury of TCE-sensitized BALB/c mice.

Bradykinin receptor in immune-mediated renal tubular injury in trichloroethylene-sensitized mice: Impact on NF-κB signaling pathway.

Trichloroethylene (TCE) is known to induce skin disorders and multi-system dysfunction, but the mechanism of this multi-organ injury is not entirely clear. It was shown in a previous study that levels of pivotal end-products of the kallikrein-kinin system (KKS), i.e. bradykinin (BK) and BK receptors B1R/B2R, in the kidneys were increased by TCE exposure. Unfortunately, how BK and its receptors acted in the etiology of the induced renal injury is not clear. Thus, this study explored any correlation between BK receptors and immune renal injury in TCE-sensitized mice by blocking the BK receptors B1R/B2R. BALB/c mice were sensitized (via skin) by TCE, with or without pre-treatment with a B1R or B2R antagonist. Renal lesions, increased expressions of B1R, B2R, Kim-1, Lipocalin-2, and NF-κB p65 subunit on tubular epithelial cells were all observed in TCE-sensitized mice. Serum levels of creatinine (Cr), microglobulin α1 and ß2, along with mRNA levels for inflammatory cytokines and NF- κB p65 in kidneys, were all increased by 72 h after a final challenge. Highly selective antagonist pre-treatment blocked B2R and significantly attenuated TCE-induced changes. Blocking B1R or B2R attenuated release of pro-inflammatory cytokines and activation of NF-κB signaling pathway (as reflected in lower up-regulation of pIκB and nuclear NF-κB p65 subunit, and down-regulation of IκB in the kidneys. These results provided evidence that TCE-sensitization caused KKS activation and enhanced the expression of B1R and B2R on tubular epithelial cells. This, in turn, accelerated NF-κB signaling pathway activation and amplified inflammatory cytokine release, which all likely contributed to TCE-induced immune renal injury.

Trichloroethylene Alters Th1/Th2/Th17/Treg Paradigm in Mice: A Novel Mechanism for Chemically Induced Autoimmunity.

The role of environmental factors in autoimmune diseases has been increasingly recognized. While major advance has been made in understanding biological pathogen-induced autoimmune diseases, chemically triggered autoimmunity is poorly understood. Trichloroethylene (TCE), a common environmental pollutant, has recently been shown to induce autoimmunity. This study explored whether TCE could cause imbalance of T helper (Th) cell subsets which would contribute to the pathogenesis of TCE-induced medicamentosa-like dermatitis. BALB/c mice were treated with TCE via drinking water at doses of 2.5 or 5.0 mg/mL for 2, 4, 8, 12, and 16 weeks. Trichloroethylene exposure caused time- and dose-dependent increase in Th1, Th2, and Th17 and decrease in regulatory cell (Treg) in the spleen at 2, 4, 8, 12, and 16 weeks, with greatest changes mainly at 4 weeks. These effects were mirrored by similar changes in the expression of their corresponding cytokines interferon-γ, interleukin 4 (IL-4), IL-17A, and IL-10. Mechanistically, these phenotypic changes were accounted for by alterations to their respective master transcription factors T-box expressed in T cells, GATA-binding protein 3, Retinoic acid-related orphan receptor ct (RORct), and forkhead box P3. Of interest, TCE treatment shifted the ratios of Th1/Th2 and Th17/Treg; specifically, TCE increased Th17/Treg. These findings provide the first evidence that TCE exposure significantly changes the Th1/Th2/Th17/Treg paradigm and their specific cytokines driven by altered master transcription factors. This may promote autoimmune reactions in the pathogenesis of TCE-induced skin sensitization and associated damage to other tissues.

Viral mimic polyinosine-polycytidylic acid potentiates liver injury in trichloroethylene-sensitized mice - Viral-chemical interaction as a novel mechanism.

Occupational trichloroethylene (TCE) exposure can induce hypersensitivity dermatitis and severe liver injury. Recently, several clinical investigations indicate that viral infection, such as human herpesvirus-6, is associated with hepatic dysfunction in patients with TCE-related generalized skin disorders. However, whether viral infection potentiates TCE-induced liver injury remains unknown. This study aimed to explore the contribution of viral infection to the development of TCE-sensitization-induced liver injury in BALB/c mice. Female BALB/c mice were randomly assigned into four groups: solvent control group (n = 20), TCE group (n = 80), poly(I:C) group (n = 20) and combination of TCE and poly(I:C) (poly(I:C)+TCE) group (n = 80). Poly(I:C) (50 µg) was i.p. administrated. TCE and poly(I:C)+TCE groups were further divided into sensitization and non-sensitization subgroup. Complement 3 and C3a protein levels, and complement factors were measured. Combination treatment significantly enhanced TCE-induced liver injury, decreased complement 3, but increased C3a in serum and liver tissues in sensitization group. These changes were not correlated with the hepatic complement 3 transcription. Moreover, combination treatment specifically promoted complement factor B, but not factor D and factor H expressions. These data provide first evidence that poly(I:C) potentiates liver injury in BALB/c mouse model of TCE-sensitization. Upregulated C3a and factor B contributes to the poly(I:C) action in TCE-induced liver injury. This new mode of action may explain increased risk of chemical-sensitization induced tissue damage by viral infection.

Role of selective blocking of bradykinin B1 receptor in attenuating immune liver injury in trichloroethylene-sensitized mice.

Trichloroethylene (TCE) is able to induce trichloroethylene hypersensitivity syndrome (THS) with multi-system immune injuries. In our previous study, we found kallikrein-kinin system (KKS) activation, including the bradykinin B1 receptor (B1R), which contributed to immune organ injury in TCE sensitized mice. However, the mechanism of B1R mediating immune dysfunction is not clarified. The present study initiates to investigate the potential mechanism of B1R on liver injury. We establish a TCE sensitized BALB/c mouse model to explore the mechanism with or without a B1R inhibitor R715. We found B1R expression was increased in TCE sensitization-positive mice. As expect, hepatocyte intracellular organelles and mitochondria disappeared, glycogen particles reduced significantly as well in TCE sensitization-positive mice via the transmission electron microscopic examination, meanwhile, R715 alleviated the deteriorate above. The blockade of B1R resulted in a significant decreased p-ERK1/2 and increased p-AKT expression. The expression of CD68 kupffer cell and its relative cytokine, including IL-6 and TNF-α, increased in TCE sensitization-positive mice and decreased in R715 pretreatment TCE sensitization-positive mice. Together, the results demonstrate B1R plays a key role in ERK/MAPK and PI3K/AKT signal pathway activation and inflammation cytokine expression in immune liver injury induced by TCE. B1R exerts a pivotal role in the development of TCE induced liver injury.

The immune response in trichloroethylene hypersensitivity syndrome: A review.

Trichloroethylene (TCE) has been used for a variety of industrial and consumer cleaning purposes because of its ability to dissolve organic substances. The multisystem injuries include those of skin, liver, and kidney, which are defined as TCE hypersensitivity syndrome (THS). THS is a serious occupational health issue. However, the mechanism of immune dysfunction leading to organ injury is poorly understood. Many studies reveal that skin lesions and organ injury caused by TCE are consistent with type IV hypersensitivity, also called delayed hypersensitivity, mediated by T cells. However, many researchers found T cell-mediated type IV hypersensitivity could not account for the pathogenesis of THS fully. Humoral immunity, including immunoglobulins and complement activation, may also play a possible role in THS pathogenesis. This review will describe the history, current understanding, and future research directions of the mechanism of THS.

The Effect of Intravenous Immunoglobulin Combined with Corticosteroid on the Progression of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Meta-Analysis.

BACKGROUND: Intravenous immunoglobulin (IVIG) treatment is commonly used to treat Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with controversial therapeutic effect. METHODS: We conducted a comprehensive meta-analysis through combining the published eligible studies to evaluate the effectiveness of IVIG on SJS and TEN treatment. RESULTS: A total of 26 studies were selected from public available databases. The combination of IVIG and corticosteroid markedly reduced the recovery time (by 1.63 days, 95% CI: 0.83-2.43, P < 0.001), compared with solo corticosteroid group. The favorable effects were greater in Asian (2.19, 95% CI: 1.41-2.97, P < 0.001), TEN (2.56, 95% CI: 0.35-4.77, P = 0.023) and high-dose IVIG treated individuals (1.78, 95% CI: 0.42-3.14, P = 0.010). The hospitalization length reduced by 3.19 days (95% CI: 0.08-6.30, P = 0.045), though the outcome was proven to be unstable. We found heterogeneities, which sources were probably regional factors. Besides, IVIG was inclined to decrease SJS/TEN mortality (SMR: 0.84, 95% CI: 0.66-1.08, P = 0.178). This impact was possibly more profound when patients were treated with high dose IVIG (SMR: 0.74, 95% CI: 0.50-1.08, P = 0.116), or when patients were diagnosed as TEN (SMR: 0.68, 95% CI: 0.45-1.01, P = 0.058). CONCLUSIONS: Our current meta-analysis suggests that IVIG combined with corticosteroid could reduce recovery time for SJS and TEN. This effect is greater among Asian patients. Whereas, its impact on reducing mortality is not significant.

Prognostic value of hematological parameters in patients with paraquat poisoning.

Paraquat (PQ) is a non-selective contact herbicide, and acute PQ poisoning has a high mortality. The aim of the present study is to evaluate the prognostic value of hematological parameters in patients with acute PQ poisoning. We retrospectively reviewed the records of patients with acute PQ poisoning from January 2010 to December 2015 at the First Affiliated Hospital, Anhui Medical University (Hefei, China). A total of 202 patients were included in the study, and the 30-day mortality was 51.98%. Leukocyte, neutrophil counts and neutrophil-lymphocyte ratio (NLR) were significantly higher in non-survivors than in survivors. In the receiver operating characteristic (ROC) curve analysis, the NLR had an area of 0.916(95%CI, 0.877-0.954) and the optimal cut-off value was 10.57 (sensitivity, 86.70%; specificity, 83.51%; Youden's index, 0.702). The leukocyte counts had an area of 0.849(95%CI, 0.796-0.902) and the optimal cut-off value was 13.15 × 103/mm3 (sensitivity, 77.10%; specificity, 83.50%; Youden's index, 0.606). The neutrophil counts had an area of 0.878(95%CI, 0.830-0.925) and the optimal cut-off value was 10.10 × 103/mm3 (sensitivity, 83.80%; specificity, 79.38%; Youden's index, 0.632). NLR, leukocyte and neutrophil counts are associated with the 30-day mortality, which may be useful and simple parameters in predicting the prognosis of PQ poisoning.

Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice.

Trichloroethylene (TCE) is a major environmental pollutant. An immunological response is a newly-recognized mechanism for TCE-induced kidney damage. However, the role of the plasma kallikrein-kinin system (KKS) in immune-mediated kidney injury has never been examined. This study aimed to explore the role of the key components of the KKS, i.e. plasma kallikrein (PK), bradykinin (BK) and its receptors B1R and B2R, in TCE-induced kidney injury. A mouse model of skin sensitization was used to explore the mechanism of injury with or without a PK inhibitor PKSI. Kidney function was evaluated by measuring blood urea nitrogen (BUN) and creatinine (Cr) in conjunction with histopathologic characterization. Plasma BK was determined by ELISA; Renal C5b-9 membrane attack complex was evaluated by immunohistochemistry. Expression of BK and PK in the kidney was detected by immunofluorescence. mRNA and protein levels of B1R and B2R were assessed by real-time qPCR and Western blot. As expected, numerous inflammatory cell infiltration and tubular epithelial cell vacuolar degeneration were observed in TCE-sensitized mice. Moreover, serum BUN and Cr and plasma BK were increased. In addition, deposition of BK, PK and C5b-9 were observed and B1R and B2R mRNA and proteins levels were up-regulated. Pre-treatment with PKSI, a highly selective inhibitor of PK, alleviated TCE-induced renal damage. In addition, PKSI attenuated TCE-induced up-regulation of BK, PK and its receptors and C5b-9. These results provided the first evidence that activation of the KKS contributed to immune-mediated renal injury induced by TCE and also helped to identify the KKS as a potential therapeutic target for mitigating chemical sensitization-induced renal damage.