Liver Inflammation Response Research Articles

Polystyrene nanoplastics potentiate the development of hepatic fibrosis in high fat diet fed mice.

Polystyrene nanoparticles (PS-NPs) as an issue of global environmental concern, have been shown to induce hepatic toxicity via triggering oxidative injury and inflammation. Non-alcoholic fatty liver disease (NAFLD) is initiated when excessive lipid is accumulated in the liver and will proceed to liver fibrosis with repeatedly chronic liver injury. In this study, we examined whether intravenous injection of PS-NPs could enhance the hepatic toxicity and potentiate the development of liver fibrosis in experimental high fat diet (HFD)-induced mice. The results demonstrated that PS-NPs could aggravate chronic hepatitis by interfere with liver lipid metabolism in HFD induced mice. Further, hepatic tissue in PS-NPs treated HFD mice displayed substantially lowered superoxide dismutase (SOD) activity, which confirming the oxidative stress induced by PS-NPs. PS-NPs exposure also resulted in the up-regulation of inflammation response in liver, as evidenced by the enhanced infiltration of Kupffer cells (KCs) and elevated expression of pro-inflammatory related indicators. Meanwhile, Masson trichrome staining revealed that PS-NPs could aggravate steatohepatitis with higher collagen fiber in HFD fed mice. Our data suggests that PS-NPs can induce oxidative stress and inflammation in HDF-induced experimental mice and further aggravate liver fibrosis, which highlight the potential health risks of PS-NPs.

Effects of dietary chitosan oligosaccharides on oxidative stress and inflammation response in liver and spleen of yellow-feather broilers exposed to high ambient temperature

Heat stress jeopardised animal health by inducing oxidative stress and inflammation. This study was done to investigate the effects of chitosan oligosaccharides (COS) on oxidative stress and inflammation response in liver and spleen of yellow-feather broilers under high ambient temperature. A total of 144 35-day-old female Chinese indigenous yellow-feather broilers (body weight 450.21 ± 10.05 g) were randomly allocated into 3 dietary treatments with 6 replication pens, each pen had 8 broilers. The treatments were: Control, basal diet; COS100, basal diet with 100 mg/kg COS; COS200, basal diet with 200 mg/kg COS. During day 22 to 42 (57 to 77 days of age), broilers in the COS200 group had higher (p < .05) ADFI than broilers in the Control group. Broilers in the COS200 group had lower (p < .05) serum alanine aminotransferase, aspartate aminotransferase, and tumour necrosis factor-α levels, and spleen malondialdehyde (MDA) content, but had higher (p < .05) liver superoxide dismutase activity and serum interleukin-10 level than broilers in the Control group. Broilers in the COS100 and COS200 groups had lower (p < .05) serum and liver MDA content, and serum interleukin-1β level, but had higher (p < .05) serum glutathione peroxidase activity than broilers in the Control group. In conclusion, dietary COS supplementation can alleviate heat stress-induced oxidative stress and inflammation response in liver and spleen by decreasing lipid peroxidation, increasing anti-oxidant enzyme activities and IL-10 level. HIGHLIGHTS Dietary COS decreased serum ALT, AST, IL-1β, TNF-α and MDA. Dietary COS increased serum GSH-Px and IL-10, liver SOD, and spleen GSH-Px.

Semen hoveniae extract ameliorates alcohol-induced chronic liver damage in rats via modulation of the abnormalities of gut-liver axis

BackgroundHovenia dulcis Thunb. is considered as a traditional herbal medicine that has been used in the treatment for ethanol-induced liver disease for centuries. Recently, substantial studies demonstrated that Semen hoveniae extract (SHE) not only suppressed the hepatic steatosis caused by chronic ethanol exposure, but also inhibited lipopolysaccharide-stimulated inflammatory responses. Nevertheless, the underlying molecular mechanisms largely remained elusive. AimTo determine the hepatoprotective effects of SHE on ethanol-triggered liver damage and further elucidate its potential mechanisms. MethodsIn the present study, the Sprague-Dawley rats were fed with the Lieber–DeCarli diet containing alcohol or isocaloric maltose dextrin as control diet with or without SHE (300 and 600 mg/kg/d bw) for 8 weeks. The levels of serum biomarkers (ALT, AST and LDH) and LPS were detected by biochemical assay kits and endotoxin detection LAL kit, respectively. The histopathological changes of liver and intestinal tissues were observed by hematoxylin and eosin (H&E) staining and Transmission electron microscope (TEM). The expressions of CD14, TLR4, MyD88, NF-κB, Iκ-B, P-Iκ-B and TNF-α in liver, and ZO-1 and occludin in intestine were determined by western blot. The faecal microbial composition was determined by16S rRNA Gene Sequencing Analysis. ResultsBiochemical and histopathological analysis revealed that SHE significantly alleviated the lipid deposition and inflammation response in liver induced by ethanol. SHE remarkably inhibited the TLR4 pathway and its downstream inflammatory mediators, and up-regulated the expressions of ZO-1 and occludin in the intestine. The further investigations suggested SHE dramatically reversed ethanol-induced alterations in the intestinal microbial flora and decreased the generation of gut-derived endotoxin. ConclusionIn summary, SHE probably modulated abnormalities of gut-liver axis and inhibited TLR4-associated inflammatory mediators activation to exert its hepatoprotective properties. These findings suggested that SHE as a traditional therapeutic options which may play an essential role in protecting against the chronic ethanol-triggered liver injury.

Hepatoprotective effect of ginsenoside Rg1 from Panax ginseng on carbon tetrachloride-induced acute liver injury by activating Nrf2 signaling pathway in mice.

Oxidative stress and inflammatory response are well known to be involved in the pathogenesis of acute liver injury. This study was performed to examine the hepatoprotective effect of ginsenoside Rg1 (Rg1) against CCl4 -induced acute liver injury, and further to elucidate the involvement of Nrf2 signaling pathway in vivo and in vitro. Mice were orally administered Rg1 (15, 30, and 60 mg/kg) or sulforaphane (SFN) once daily for 1 week prior to 750 μL/kg CCl4 injection. The results showed that Rg1 markedly altered relative liver weights, promoted liver repair, increased the serum level of TP and decreased the serum levels of ALT, AST and ALP. Hepatic oxidative stress was inhibited by Rg1, as evidenced by the decrease in MDA, and increases in GSH, SOD, and CAT in the liver. Further research demonstrated that Rg1 suppressed liver inflammation response through repressing the expression levels of inflammation-related genes including TNF-α, IL-1β, IL-6, COX-2, and iNOS. In addition, Rg1 enhanced antioxidative stress and liver detoxification abilities by up-regulating Nrf2 and its target-genes such as GCLC, GCLM, HO-1, NQO1, Besp, Mrp2, Mrp3, Mrp4, and down-regulating Cyp2e1. However, the changes in Nrf2 target-genes, as well as ameliorative liver histology induced by Rg1 were abrogated by Nrf2 antagonist all-transretinoic acid in vivo and Nrf2 siRNA in vitro. Overall, the findings indicated that Rg1 might be an effective approach for the prevention against acute liver injury by activating Nrf2 signaling pathway.

Blocking Notch signal in myeloid cells alleviates hepatic ischemia reperfusion injury by repressing the activation of NF-κB through CYLD.

Ischemia-reperfusion (I/R) is a major reason of hepatocyte injury during liver surgery and transplantation. Myeloid cells including macrophages and neutrophils play important roles in sustained tissue inflammation and damage, but the mechanisms regulating myeloid cells activity have been elusive. In this study, we investigate the role of Notch signaling in myeloid cells during hepatic I/R injury by using a mouse model of myeloid specific conditional knockout of RBP-J. Myeloid-specific RBP-J deletion alleviated hepatic I/R injury. RBP-J deletion in myeloid cells decreased hepatocytes apoptosis after hepatic I/R injury. Furthermore, myeloid-specific RBP-J deletion led to attenuated inflammation response in liver after I/R injury. Consistently, Notch blockade reduced the production of inflammatory cytokines by macrophages in vitro. We also found that blocking Notch signaling reduced NF-κB activation and increased cylindromatosis (CYLD) expression and knockdown of CYLD rescued reduction of inflammatory cytokines induced by Notch blockade in macrophages during I/R injury in vitro. On the other hand, activation of Notch signaling in macrophages led to increased inflammatory cytokine production and NF-κB activation and decreased CYLD expression in vitro. These data suggest that activation of Notch signaling in myeloid cells aggravates I/R injury, by enhancing the inflammation response by NF-κB through down regulation of CYLD.

Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach.

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

Immunopathologic effects of scorpion venom on hepato-renal tissues: Involvement of lipid derived inflammatory mediators

Scorpion venoms are known to cause different inflammatory disorders through complex mechanisms in various tissues. In the study here, the involvement of phospholipase A2 (PLA2) and cyclo-oxygenase (COX)-derived metabolites in hepatic and renal inflammation responses were examined. Mice were envenomed with Androctonus australis hector scorpion venom in the absence or presence of inhibitors that can interfere with lipid inflammatory mediator synthesis, i.e., dexamethasone (PLA2 inhibitor), indomethacin (non-selective COX-1/COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor). The inflammatory response was assessed by evaluating vascular permeability changes, inflammatory cell infiltration, oxidative/nitrosative stress marker levels, and by histologic and functional analyses of the liver and kidney. Results revealed that the venom alone induced an inflammatory response in this tissues marked by increased microvascular permeability and inflammatory cell infiltration, increases in levels of nitric oxide and lipid peroxidation, and decreases in antioxidant defense. Moreover, significant alterations in the histological architecture of these organs were associated with increased serum levels of some metabolic enzymes, as well as urea and uric acid. Pre-treatment of mice with dexamethasone led to significant decreases of the inflammatory disorders in the hepatic parenchyma; celecoxib pre-treatment seemed to be more effective against renal inflammation. Indomethacin pre-treatment only slightly reduced the inflammatory disorders in the tissues. These results suggest that the induced inflammation response in liver was mediated mainly by PLA2 activation, while the renal inflammatory process was mediated by prostaglandin formation by COX-2. These findings provide additional insight toward the understanding of activated pathways and related mechanisms involved in scorpion envenoming syndrome.

Antioxidant effects of the Uygur herb, Foeniculum Vulgare Mill, in a rat model of hepatic fibrosis

To evaluate therapeutic and antioxidant effects of Uygur Herb Foeniculum Vulgare Mill (FVM) in hepatic fibrosis rats. Hepatic fibrosis model was built in rats by subcutaneous injection with 40% CCl4 olive oil mixture. At the same time the rats were given high lipoid-low protein animal feeds for 5 weeks. 94 male SD rats were randomly divided into six groups :blank control group (A-group), 8 rats were feed in normal; prevention model control group (B-group), 10 rats were given saline solution by intragastric administration during make of hepatic fibrosis model; FVM prevention group (C-group), 10 rats were given FVM by intragastric administration during make of hepatic fibrosis model; model control group (D-group), FVM treatment group (E-group); Fuzhenghuayu treatment group (F-group). 22 rats in each D, E, F-group were respectively given saline solution, FVM and Fuzhenghuayu by intragastric administration after hepatic fibrosis model were built. At the 5-th weekend, A, B, C- group rats were sacrificed. At the 6-th, 7-th, 8-th, 9-th weekend, 4-6 rats in D, E, F-group were sacrificed. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN) and 8 - hydroxy-2-deoxyguanosine (8-OHdG) were detected, liver tissue homogenate superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) were detected. Histopathologic changes were observed after H.E and Masson staining. The expression of alpha-smooth muscle actin(a-SMA) were detected by immunohistochemical staining. The data were analyzed by SPSS17.0 software. The serum levels of ALT, AST, HA, and LN in the FVM prevention group were significantly reduced compared to the prevention model control group.(P less than 0.05). Rats in FVM treatment group appeared a marked lower serum levels of ALT, AST, HA compared to the model control group (P less than 0.05), and a distinguished lower Inflammation grade and fibrosis stage (P less than 0.05) when the liver section were assayed as well; Rats in FVM treatment group and FVM prevention group had a conspicuous lower content of MDA, 8-OHdG, fibre and a-SMA expression (P less than 0.05), a significantly higher level of SOD, GSH-Px compared to those of in the model control groups. Foeniculum Vulgare Mill declines liver inflammation response ,and prevent the hepatic fibrosis progression,, this may be due to its effects of antioxidative results.

Effect of interferon-α on rat liver fibrosis induced by CCl(4)

To explore the curative effect and the underlying mechanism of interferon-α (IFN-α) on rat liver fibrosis induced by CCl(4). Forty-five Wistar male rats were randomly divided into 3 groups: a normal control group (n=15), a liver fibrosis group (n=15) and a IFN-α treatment group (n=15). The rats of the control group and the liver fibrosis group received peanut oil (0.2 mL/100 g body weight), twice a week for 8 weeks. The rats of the liver fibrosis group and the IFN-α treatment group were received intraperitoneal injection of 50% CCl(4) (CCl(4):peanut oil=1:1, 0.2 mL/100 g body weight, ip) or IFN-α (CCl(4):peanut oil=1:1, 0.2 mL/100 g body weight, ip), twice a week for 8 weeks. In the 9th week, the rats of IFN-α treatment group were switch to receive IFN-α at 100 000 units (s.c.) per day for 3 weeks. The rats were all sacrificed in the 11th week. Pathological changes of liver, semi-quantitative scoring of rat liver was observed. Tissue hydroxyproline, the mRNA expression of Collagen I, Collagen III, transforming growth factor-beta 1 (TGF-β1), connective tissue growth factor (CTGF), a-smooth muscle actin (α-SMA), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) of rat liver was detected. The protein expression of MMP-9 and TIMP-1 also was detected. Semi-quantitative scoring of inflammation,semi-quantitative scoring of liver fibrosis, hydroxyproline and collagen in the IFN-α treatment group were significantly lower than those in the liver fibrosis group (all P<0.05). The mRNA expression of TGF-β1, CTGF, α-SMA and TIMP-1, and the protein expression of TIMP-1 in the IFN-α treatment group were significantly lower than those in the liver fibrosis group (all P<0.05). But there was no significant difference in MMP-9 between the IFN-α treatment group and the liver fibrosis group. IFN-α can decrease the liver fibrogenesis induced by CCl(4) in rats and reduce liver inflammation response. The anti-fibrosis effect of IFN-α may be related to decrease in TGF-β1, CTGF and TIMP-1 expression and to inhibiting of the hepatic satellite cells' activation and extracellular matrix synthesis.

Effects of Subchronic Exposure to Multi-Walled Carbon Nanotubes on Mice

Carbon nanotubes have attracted attention not only due to electrical, optical, and mechanical applications but also due to their presence in biological and pharmaceutical products. In this study, modified multi-walled carbon nanotubes (MWCNT) were used as a model to evaluate potential subchronic effects of carbon nanotubes on mice. ICR mice were treated with phosphorylcholine-grafted multi-walled carbon nanotubes (MWCNT-PC) daily for 28 d at 10, 50, or 250 mg/kg by the intraperitoneal (ip) route. Subchronic exposure to MWCNT-PC did not produce any apparent systemic effects in mice. The body weight of the high-dose group was significantly lower than control in male mice, whereas tissue to body weight ratios of liver, spleen, and lung rose significantly with increase of dose of MWCNT-PC. There were significant differences between high-dose exposure and control groups. Accumulation of carbon nanotubes and inflammation response in liver, spleen, and lung were observed in the high-dose exposure group. No systemic toxicity and histopathological changes were found in 10-mg/kg exposure groups. Data in the present study support the view that MWCNT in vivo do not exert apparent marked effects in mice and that MWCNT products are relatively safe for human consumption.

Metabolomics investigation of exercise-modulated changes in metabolism in rat liver after exhaustive and endurance exercises

Exhaustive exercise and endurance exercise training modify the physiological status of the body differently. The present study aimed to evaluate the alteration in biochemical composition with exhaustive and endurance exercises in rats using metabolomics strategy. The metabolite profile of liver tissue was investigated on gas chromatography-mass spectrometry (GC-MS). Data further underwent partial least-squares-discriminant analysis (PLS-DA) to compare the effects on metabolites in sedentary control, exhaustively exercised and endurance trained rats. GC-MS detected 115 highly reproducible peaks in chromatograms from individual liver tissue extracts, and we identified 55 of them. The three groups showed significant differences in metabolic profile. Changes in liver metabolism involved metabolites such as amino acids, fatty acids, organic acids, and carbohydrates. Endurance training elevated the greater rate of tricarboxylic acid cycle and antioxidant activity, and exhaustive exercise led to accumulated urea markers and an inflammation response in liver. In addition, GC-MS-based metabolomic analysis is a promising tool to investigate a pathological status with different exercise programs.

Small Interfering RNA Targeting Heme Oxygenase-1 (HO-1) Reinforces Liver Apoptosis Induced by Ischemia–Reperfusion Injury in Mice: HO-1 Is Necessary for Cytoprotection

We have shown that overexpression of heme oxygenase-1 (HO-1) prevents the liver inflammation response leading to ischemia and reperfusion injury (IRI). This study was designed to explore the precise function and mechanism of HO-1 cytoprotection in liver IRI by employing a small interfering RNA (siRNA) that effectively suppresses HO-1 expression both in vitro and in vivo. Using a partial lobar liver warm ischemia model, mice were injected with HO-1 siRNA/nonspecific control siRNA or Ad-HO-1/Ad-beta-gal. Those treated with HO-1 siRNA showed increased serum glutamic-oxaloacetic transaminase levels, significant liver edema, sinusoidal congestion/cytoplasmic vacuolization, and severe hepatocellular necrosis. In contrast, Ad-HO-1-pretreated animals revealed only minimal sinusoidal congestion without edema/vacuolization or necrosis. Administration of HO-1 siRNA significantly increased local neutrophil accumulation and the frequency of apoptotic cells. Mice treated with HO-1 siRNA were characterized by increased caspase-3 activity and reduced HO-1 expression, whereas those given Ad-HO-1 showed decreased caspase-3 activity and increased HO-1/Bcl-2/Bcl-x(L), data confirmed by use of an in vitro cell culture system. Thus, by using an siRNA approach this study confirms that HO-1 provides potent cytoprotection against hepatic IRI and regulates liver apoptosis. Indeed, siRNA provides a powerful tool with which to study gene function in a wide range of liver diseases.

CXCL10 regulates liver innate immune response against ischemia and reperfusion injury

We have shown that activation of toll-like receptor 4 (TLR4) and its interferon regulatory factor 3 (IRF3)-dependent downstream signaling pathway are required for the development of liver ischemia/reperfusion injury (IRI). This study focused on the role of TLR4-IRF3 activation pathway products, in particular, chemokine (C-X-C motif) ligand 10 (CXCL10). The induction of CXCL10 by liver IR was rapid (1 hour postreperfusion), restricted (ischemic lobes), and specific (no CXCL9 and CXCL11 induction). Functionally, CXCL10 was critical for IR-induced liver inflammation and hepatocellular injury. CXCL10 knockout (KO) mice were protected from IRI, as evidenced by reduced serum alanine aminotransferase (sALT) levels and preserved liver histological detail. The induction of pro-inflammatory genes, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, and IL-12beta was diminished, whereas the induction of the IL-10 gene remained intact in CXCL10 KO mice, indicating an altered liver response against IR. This was accompanied by selective down-regulation of extracellular signal-regulated kinase (ERK), but intact Jun N-terminal kinase (JNK), activation in the KO IR livers. This altered liver inflammation response was (1) specific to IR, because lipopolysaccharide (LPS) induced a comparable pro-inflammatory response in CXCL10 KO and wild-type (WT) mice; and (2) responsible for liver cytoprotection from IR, because neutralization of IL-10 restored local inflammation and hepatocellular damage. CXCL10 regulates liver inflammation response against IRI, and its deficiency protected livers from IRI by local IL-10-mediated cytoprotection. Targeting CXCL10 may provide a novel therapeutic means to ameliorate liver IRI in clinics.