interleukin-8 and Cholestasis

Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.. The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.

Topics: Animals; Animals, Newborn; Biliary Atresia; Biomarkers; Cholestasis; Diagnosis, Differential; Disease Models, Animal; Female; Genome-Wide Association Study; Humans; Infant; Infant, Newborn; Interleukin-8; Laminin; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Prospective Studies; Receptors, Interleukin-8B; Sensitivity and Specificity

To investigate the effect of salvia miltiorrhiza and shengmai (SS) on inflammatory mediator and renal function in patients with obstructive jaundice (OJ).. This study included three groups: the OJ patients receiving SS for 6 days after operation (the SS group, n = 15); the OJ patients not receiving SS (the OJ group, n = 15); the patients with other hepato-biliary disorders (the Non-OJ group, n = 15). The levels of ET, LPs, TNF-alpha, IL-6, IL-8 and urine RBP, TFR, ALB were measured one day before operation and 1, 4, 7 days after operation.. The SS group's LPs, TNF-alpha, IL-6, IL-8, ET, RBP, TFR and ALB levels were obviously lower on Day 7 after operation as compared with those on Day 1 after operation (P < 0.05). The urine RBP and ALB levels were significantly lower in the SS group than in the OJ group (P < 0.05).. The post-operative use of salvia miltiorrhiza and shengmai for patients with obstructive jaundice may effectively decrease the postoperative levels of plasma LPs, ET, TNF-alpha, IL-6 and IL-8. At the same time, salvia miltiorrhiza and shengmai may protect renal function by inhibiting inflammatory mediator and improving blood dynamics.

Topics: Adult; Aged; Cholestasis; Drug Combinations; Drugs, Chinese Herbal; Endotoxins; Female; Humans; Interleukin-6; Interleukin-8; Kidney Function Tests; Male; Middle Aged; Panax; Phytotherapy; Plant Extracts; Salvia miltiorrhiza; Tumor Necrosis Factor-alpha

Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.. A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS.. Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.

Topics: Alagille Syndrome; Biomarkers; Child; Cholestasis; Elasticity Imaging Techniques; Endoglin; Humans; Interleukin-8; Liver; Liver Cirrhosis; Liver Diseases; Matrix Metalloproteinase 7

Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8.

Topics: Animals; Apoptosis; Bile Acids and Salts; Cholestasis; DNA Methylation; Hepatocytes; Humans; Inflammation; Interleukin-8; Liver Diseases; Mice; Necroptosis; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases

Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and liver fibrosis. The early diagnosis of BA is still challenging. This study aimed to evaluate the diagnostic values of matrix metalloprotease-7 (MMP-7), interleukin-8 (IL-8), and gamma-glutamyl transferase (GGT) in BA. Infants diagnosed with BA and non-BA between 2013 and 2018 were retrospectively analyzed. Plasma levels of MMP-7, IL-8, and GGT were measured in these infants. The receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were used to assess the diagnostic values of MMP-7, IL-8, and GGT. The expression of MMP-7 and IL-8 in the livers was detected by immunofluorescence staining. A total of 229 infants were enrolled in this study: 156 BA infants and 73 non-BA infants including 16 ones with infantile hepatitis syndrome. The plasma levels of MMP-7, IL-8, and GGT in BA infants had a median of 11.8 ng/mL (interquartile range, IQR: 5.3-57.5), 1.5 ng/mL (IQR: 1.0-2.8), and 381.0 U/L (IQR: 197.0-749.0), respectively, which were higher than non-BA subjects [MMP-7, 4.4 ng/mL (IQR: 3.3-6.1); IL-8, 0.7 ng/mL (IQR: 0.5-1.0); GGT, 59.0 U/L (IQR: 26.0-124.0)]. The AUC values of MMP-7, IL-8, and GGT for the diagnosis of BA were 0.8035, 0.8083, and 0.9126, respectively. The AUC values of MMP-7 + IL-8, MMP-7 + GGT, IL-8 + GGT, and MMP-7 + IL-8 + GGT for the diagnosis of BA were 0.8248, 0.9382, 0.9168, and 0.9392, respectively. The AUC values of MMP-7, IL-8, and GGT for differentiating BA infants with cholic stool from non-BA infants with cholic stool were 0.8006, 0.8258, and 0.9141, respectively. The expression of MMP-7 and IL-8 was increased in the cholangiocytes in BA livers.   Conclusion: Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA and may be reliable biomarkers for BA. What is Known: • Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and progressive liver fibrosis. • Although early diagnosis of BA is crucial for good outcomes, it remains a clinical challenge. What is New: • Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA. • Plasma MMP-7, IL-8, and GGT have good accuracy for differentiating BA infants with cholic stool from non-BA infants with cholic stool.

Topics: Biliary Atresia; Biomarkers; Child; Cholestasis; gamma-Glutamyltransferase; Humans; Infant; Interleukin-8; Liver Cirrhosis; Matrix Metalloproteinase 7; Retrospective Studies

Although the exact etiology of biliary atresia (BA) is still elusive, inflammation plays a key role. Release of proinflammatory cytokines from activated immune cells perpetuates the injury and causes biliary destruction. We aimed to study interleukin (IL)-2 and IL-8 expression in liver tissue of BA patients compared with other neonatal cholestatic disorders.. The study included 59 infants with neonatal cholestasis in two groups; BA group (n=31) and non-BA group (n=28) with cholestatic disorders other than BA as controls. Demographic, clinical, laboratory, and histopathological parameters were collected. IL-2 and IL-8 immunostaining was performed. Immunostaining in portal cellular infiltrate was scored as positive or negative and expressed as the mean cell count in three portal tracts.. The mean value of IL-2 and IL-8 positive inflammatory cells was significantly higher in BA than in non-BA group (P-values of 0.004 and 0.002 respectively). IL-2 correlated significantly with IL-8 immunostaining in both BA and non-BA group (P<0.0001 for both). Furthermore, both cytokines in both groups correlated significantly with inflammatory activity in liver biopsy while there was no significant correlation with the other studied parameters. Yet, there was a trend of increased expression of IL-2 and IL-8 with increasing stage of fibrosis in BA group. This trend was not observed in non-BA group.. The significantly higher expression of IL-2 and IL-8 in patients with BA compared to non-BA suggests a potential role for these cytokines in the pathogenesis in therapy of this devastating neonatal hepatic disorder.

Topics: Biliary Atresia; Cholestasis; Female; Ferritins; Humans; Infant; Infant, Newborn; Inflammation; Interleukin-2; Interleukin-8; Liver; Liver Diseases; Male; Retrospective Studies

We present here the unusual case of a male newborn infant who showed progressive severe cholestasis. The infant's gestational age was 37 weeks, and his birth weight was 2134 g. His serum level of direct bilirubin gradually increased from the 6th day of life and reached 257.5 micromol/L on the 22nd day of life. We could not find any cause for his cholestasis, but his serum level of ferritin was extremely elevated at 9211.0 ng/mL. Because we felt that his clinical condition might be related to hypercytokinemia caused by an immunologic reaction, steroid pulse therapy and cyclosporine were administered. His condition improved, and his direct bilirubin and ferritin levels declined. From the investigation of his cytokine profile, we found a preferentially elevated level of serum interleukin 17 (IL-17) (96.1 pg/mL) and high level of chemokines IL-8 and macrophage inflammatory protein 1beta. The IL-17 level gradually decreased to 7.5 pg/mL by the 124th day of life. The infant was successfully discharged from the children's hospital but later developed epilepsy at 11 months and asthma at 1 year, 2 months of age. Although we have not yet reached a definitive diagnosis, this case may be the first to show a relationship between cholestasis and an elevated serum IL-17 level in the neonatal period.

Topics: Biomarkers; Cholestasis; Cyclosporine; Disease Progression; Drug Therapy, Combination; Follow-Up Studies; Humans; Infant, Newborn; Interleukin-17; Interleukin-8; Macrophage Inflammatory Proteins; Male; Risk Assessment; Severity of Illness Index; Steroids; Treatment Outcome

Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.

Topics: Animals; Bile Ducts; Cell Proliferation; Cholestasis; Gene Expression Profiling; Hepatitis; Hepatocytes; Incidence; Infarction; Interleukin-8; Ligation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Plasminogen Activator Inhibitor 1; RNA, Messenger; Tissue Plasminogen Activator; Transcription, Genetic; Urokinase-Type Plasminogen Activator

Postoperative cholangitis is common after operation for biliary atresia. Empirical pulse therapy with glucocorticoid is effective in reversing some detrimental clinical manifestations, but the rationale for such a therapy still is not substantiated.. Adult male rats were divided into groups according to the treatment: sterile normal saline (NS) or Escherichia coli (EC, 1 mL containing 10(8) cells of ATCC 25922 strain), 1 mL, were infused into the proximal choledochostomy (PC) tube 2 weeks after ligation of the PC tube (bile duct ligation, BDL), then immediate tube-tube choledocho-choledochostomy (biliary drainage, BD) was constructed. A high dose of dexamethasone (DEX, intraperitoneal injection; 2 mg/kg of body weight) was given after BD in treatment groups. Histopathology of the liver, as well as liver chemokine mRNA expression and serum chemokine levels, were studied 24 hours after treatment.. Inflammatory cell infiltration to the liver was retarded with DEX treatment, which was correlated with a significantly lower expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) mRNA in the liver (P =.006). Serum IL-8 and MCP-1 levels were also significantly down-regulated with DEX treatment (P = 0.008).. Glucocorticoid treatment is effective in modulating IL-8 and MCP-1 expression and ameliorating inflammatory cell infiltration in rat liver with bacterial cholangitis and cholestasis.

Topics: Animals; Bacterial Infections; Biliary Atresia; Chemokine CCL2; Cholangitis; Cholestasis; Dexamethasone; Disease Models, Animal; Down-Regulation; Glucocorticoids; Interleukin-8; Liver; Male; Postoperative Complications; Rats; Rats, Sprague-Dawley

To investigate the effect of inflammatory transmitter on renal function in obstructive jaundice.. 15 patients with obstructive jaundice (OJ) as the experimental group and 15 non-joundiced patients as the control group were involved in this study. The plasma ET, LPS, TNF-alpha, IL-6, IL-8 and urine REP, TFR, ALB were measured in 15 patients with OJ before and 1, 4, 7 days after surgery and in 15 patients without jaundice as controls.. The levels of plasma ET, LPS, TNF-alpha, IL-6, IL-8 and urine RBP, TFR, ALB increased significantly at multiple time points as compared with those in the non-OJ patients (P < 0.05), and the changes of plasma ET, LPS, TNF-alpha, IL-6, IL-8 are the same as those of urine RBP, TFR, ALB.. These data suggest that there is interaction between ET, LPS, TNF-alpha, IL-6, IL-8 and the damage to renal function with OJ after surgery.

Topics: Adult; Aged; Cholestasis; Endothelins; Female; Humans; Interleukin-6; Interleukin-8; Kidney; Male; Middle Aged; Tumor Necrosis Factor-alpha

Obstructive jaundice is associated with postoperative complications related to increased endotoxaemia and the inflammatory response. In animals obstructive jaundice is associated with endotoxaemia and cytokine induction, which are reversed by internal biliary drainage.. To study endotoxaemia and the subsequent inflammatory response in obstructive jaundiced patients and after endoscopic biliary drainage.. In 15 patients with malignant distal obstructive jaundice, inflammatory and bacteriological parameters were assessed before endoscopic stent placement and after three weeks endoscopic drainage.. Drainage reduced bilirubin from 252.5 to 45.1 micromol/l. At baseline low level endotoxaemia was detected (4.3 pg/ml) which was not affected after drainage (4.5 pg/ml). Serum interleukin 8 (IL-8) and endotoxin binding proteins were increased in jaundice and reduced after drainage (IL-8 113.6 to 20.7 pg/ml; lipopolysaccharide binding protein 24.2 to 16.5 microg/ml; sCD14 17.4 to 7.6 microg/ml; bactericidal/permeability increasing protein 2.9 to 1.8 ng/ml). Levels of other cytokines, augmented in animals, were only slightly increased and not changed after drainage (tumour necrosis factor (TNF): 21.7 and 18.4 pg/ml; sTNFr p55/75: 2.9/7.0 and 2.7/5.6 ng/ml; IL-6: 4.2 and 6.1 pg/ml; IL-10: 4.5 and 2.7 pg/ml). Elastase and lactoferrin tended towards reduction after drainage. All bile cultures were positive after stenting.. The effects of obstructive jaundice in humans on endotoxin and cytokines are different from those in animal models. Obstructive jaundice causes alterations in circulating endotoxin binding proteins and IL-8. Concentrations of other mediators (TNF, previously suggested as being responsible for systemic endotoxaemia effects) are low and not affected by drainage.

Topics: Bile Duct Neoplasms; Carrier Proteins; Cholestasis; Cytokines; Drainage; Endoscopy, Gastrointestinal; Endotoxins; Humans; Interleukin-8; Leukocyte Count; Lipopolysaccharide Receptors; Neutrophil Activation; Preoperative Care

The release of cytokine by Kupffer cells during hypoxia/reoxygenation was studied in vitro in male Wistar rats with obstructive jaundice to investigate the kinetics of interleukin-8 (IL-8) release by Kupffer cells during hypoxia/reoxygenation, and to study the influence of endotoxin during the reoxygenation period. The rats were divided into two groups: one that underwent bile duct ligation (group OJ), and one that underwent a sham operation (group C). Kupffer cells were isolated by collagenase digestion and centrifugal elutriation. The cells were first subjected to hypoxia as 95% nitrogen, after which they were given reoxygenation as 95% oxygen. In addition, they were stimulated with lipopolysaccharide (LPS) 0, 1, and 10 ng/ml. In both groups, the levels of IL-8 became increased during the period of hypoxia/reoxygenation, and reoxygenation after hypoxia further intensified IL-8 production. During the period of hypoxia, the IL-8 levels in group OJ were significantly increased compared with those in group C. With the LPS challenge, there was no significant difference in IL-8 levels in either group. In conclusion, obstructive jaundice induces the activation of Kupffer cells, resulting in increased IL-8 production during hypoxia/reoxygenation.

Topics: Analysis of Variance; Animals; Bile Ducts; Cell Hypoxia; Cholestasis; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; In Vitro Techniques; Interleukin-8; Kupffer Cells; Ligation; Lipopolysaccharides; Male; Rats; Rats, Wistar

The effect of obstructive jaundice on neutrophil chemotactic function was investigated, with a potent chemotactic factor, IL-8 (recombinant rat GRO-beta), in rats that received 7-day bile duct ligation. Carrageenin or IL-8 was injected into a preformed air pouch, and exudate was collected 4 h later for measurement of myeloperoxidase activity. In vitro chemotaxis of peripheral neutrophils to IL-8 was evaluated by a modified Boyden chamber method. Both carrageenin and IL-8 induced significantly pronounced intra-air pouch neutrophil recruitment in the bile duct-ligated group compared with a sham-ligated group. In vitro neutrophil chemotaxis was significantly increased in the bile duct-ligated group compared with the sham-ligated group. The present experimental model suggests enhanced neutrophil chemotaxis to IL-8 in obstructive jaundice.

Topics: Animals; Carrageenan; Chemotaxis, Leukocyte; Cholestasis; Interleukin-8; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar

The effect of n-6 fatty acids, particularly gamma-linolenic acid (GLA), on the oxidase response and neutrophil priming by tumour necrosis factor alpha and interleukin 8 was studied in both normal volunteers and patients with obstructive jaundice. GLA inhibited the neutrophil respiratory burst at concentrations higher than 50 mummol/l, but abolished cytokine priming at concentrations as low as 1 mummol/l. Inhibition was not the result of either cytotoxicity to the neutrophils or alteration in cytosolic free calcium homoeostasis. It is concluded that GLA is a potential inhibitor of neutrophil priming by cytokines and of the oxidative response.

Topics: Aged; Aged, 80 and over; Calcium; Cholestasis; gamma-Linolenic Acid; Humans; Interleukin-8; Middle Aged; Neutrophils; Respiratory Burst; Tumor Necrosis Factor-alpha