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| 1 | Macrophage secretory products induce an inflammatory phenotype in hepatocytes显示文摘AIM:To investigate the influence of macrophages on hepatocyte phenotype and function.METHODS:Macrophages were differentiated from THP-1 monocytes via phorbol myristate acetate stimulation and the effects of monocyte or macrophageconditioned medium on HepG2 mRNA and protein expression determined.The in vivo relevance of these findings was confirmed using liver biopsies from 147 patients with hepatitis C virus(HCV)infection.RESULTS:Conditioned media from macrophages,but not monocytes,induced a transient morphological change in hepatocytes associated with upregulation of vimentin(7.8±2.5-fold,P=0.045)and transforming growth factor(TGF)-β1(2.6±0.2-fold,P<0.001)and downregulation of epithelial cadherin(1.7±0.02-fold,P=0.017)mRNA expression.Microarray analysis revealed significant upregulation of lipocalin-2(17-fold,P <0.001)and pathways associated with inflammation,and substantial downregulation of pathways related to hepatocyte function.In patients with chronic HCV,realtime polymerase chain reaction and immunohistochemistry confirmed an increase in lipocalin-2 mRNA(F0 1.0 ±0.3,F1 2.2±0.2,F2 3.0±9.3,F3/4 4.0±0.8,P= 0.003)and protein expression(F1 1.0±0.5,F2 1.3± 0.4,F3/4 3.6±0.4,P=0.014)with increasing liver injury.High performance liquid chromatography-tandem mass spectrometry analysis identified elevated levels of matrix metalloproteinase(MMP)-9 in macrophageconditioned medium,and a chemical inhibitor of MMP-9 attenuated the change in morphology and mRNA expression of TGF-β1(2.9±0.2 vs 1.04±0.1,P<0.001) in macrophage-conditioned media treated HepG2 cells.In patients with chronic HCV infection,hepatic mRNA expression of CD163(F0 1.0±0.2,F1/2 2.8±0.3,F3/4 5.3±1.0,P=0.001)and MMP-9(F0 1.0±0.4,F1/2 2.8±0.3,F3/4 4.1±0.8,P=0.011)was significantly associated with increasing stage of fibrosis.CONCLUSION:Secreted macrophage products alter the phenotype and function of hepatocytes,with increased expression of inflammatory mediators,suggesting that hepatocytes actively participate in liver injury. | Michelle Melino Victoria L Gadd Gene V Walker Richard Skoien Helen D Barrie Dinesh Jothimani Leigh Horsfall Alun Jones Matthew J Sweet Gethin P Thomas Andrew D Clouston Julie R Jonsson Elizabeth E Powell | 2012 | World Journal of Gastroenterology2012，18，15： | 3 |
| 2 | Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration显示文摘AIM:To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype(SASP).METHODS:Hydrogen peroxide treatment was used to induce senescence in the human Hep G2 hepatocyte cell line.Senescence was confirmed by cytochemical staining for a panel of markers including Ki67,p21,heterochromatin protein 1β,and senescence-associated-β-galactosidase activity.Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction(q PCR),and conditioned media was used in proteomic analyses,a human chemokine protein array,and cell migration assays to characterise the composition and function of the hepatocyte SASP.RESULTS:Senescent hepatocytes induced classical markers of senescence(p21,heterochromatin protein1β,and senescence-associated-β-galactosidase activity);and downregulated the proliferation marker,Ki67.Hepatocyte senescence induced a 4.6-fold increase in total secreted protein(P=0.06)without major alterations in the protein profile.Senescence-induced genes were identified by microarray(Benjamini Hochbergcorrected P<0.05);and,consistent with the increase in secreted protein,gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes.The hepatocyte SASP included characteristic factors such as interleukin(IL)-8 and IL-6,as well as novel components such as SAA4,IL-32and Fibrinogen,which were validated by q PCR and/or chemokine protein array.Senescent hepatocyteconditioned medium elicited migration of inflammatory(granulocyte-macrophage colony stimulating factor,GM-CSF-derived),but not non-inflammatory(CSF-1-derived)human macrophages(P=0.022),which could contribute to a pro-inflammatory microenvironment in vivo,or facilitate the clearance of senescent cells.CONCLUSION:Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis. | Katharine M Irvine Richard Skoien Nilesh J Bokil Michelle Melino Gethin P Thomas Dorothy Loo Brian Gabrielli Michelle M Hill Matthew J Sweet Andrew D Clouston Elizabeth E Powell | 2014 | World Journal of Gastroenterology2014，20，47： | 2 |
| 3 | Atmospheric deposition of PAHs,PCBs, and organochlorine pesticides to Corpus Christi Bay, Texas显示文摘 | Park J S Terry L W Sweet S | 2002 | Atmospheric Environment2002，36，： | 1 |
| 4 | Determingtion of Sulfon-amide Residues in the Tissues of Food Animals Using Automated Precolumn Derivatization and Liquid Chromatography with Fluorescence Detection显示文摘 | Salisburk C D C Sweet J C Munro R | 2004 | J AOAC Int2004，87，5： | 1 |
| 5 | Tributyltin in environmental samples from the Former Derecktor Shipyard, Coddington Cove, Newport RI显示文摘 | Wade T L Sweet S T Quinn J G Cairns R W King J W | 2004 | Environmental Pollution2004，129，2： | 1 |
| 6 | A novel pathway regulatillg lipopolysaccharide-indued shock by ST2/T1 via inhibition of loll-like receptor 4 expression显示文摘 | Sweet M J Leung BP Kang D | 2001 | J lmmunol2001，166，： | 1 |
| 7 | Chorioamnionitis and increased neonatal lung lavage fluid matrix metalloproteinase-9 levels: Implications for antenatal origins of chronic lung disease 显示文摘 | Curley AE Sweet DG Thornton CM O'hara MD Chesshyre E Pizzotti J | 2003 | Am J Obstet Gynecol2003，188，4： | 1 |
| 8 | Very small-satellite design for distributed space missions显示文摘 | Barnhart D J Vladimirova T Sweeting M N | | 0，，06： | 1 |
| 9 | An improved method to recover saliva from human skin:the double swab technique显示文摘 | Lorente M Lorente J A | 1997 | J Forensic Sci1997，42，： | 1 |
| 10 | Performance of chromogenic in situ hybridization on testing HER2 Status in breast carcinomas with chromosome 17 polysomy and equivocal (2+) herceptest results:a study of two institutions using the conventional and new ASCO/CAP scoring criteria显示文摘 | Gong Y Sweet W Duh Y J | 2009 | Am J Clin Pathol2009，132，2： | 1 |
| 11 | Some chemical reactions of 3, 9-diehloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro undeeane3,9-dioxide 显示文摘 | Ratz R Sweeting O J | 1963 | J Org Chem1963，28，3： | 1 |
| 12 | Long-term outcome after resection of brainstem hemangioblastomas in yon Hippel-Lindau disease显示文摘 | Wind J J Bakhtian KD Sweet JA | 2011 | J Neurosurg2011，114，5： | 1 |
| 13 | Dimensions of positive symptoms in late versus early onset psychosis显示文摘 | Mason O Stott J Sweeting R | 2013 | Int Psychogeriatr2013，25，2： | 1 |
| 14 | Long-term outcome after resection of brainstem hemangioblastomas in von HippelLindau disease显示文摘 | Wind J J Bakhtian K D Sweet J A | 2011 | Neurosurg2011，114，5： | 1 |
| 15 | Feeding response to central orexins显示文摘 | Sweet DC Levine AS Billington C J | 1999 | Brain Res1999，821，： | 1 |
| 16 | Atmospheric distribution of polyeyclic aromatic hydrocarbons and deposition to Galveston Bay, Texas, USA显示文摘 | Park J S Wade T L Sweet S T | 2001 | Atmospheric Environment2001，35，： | 1 |
| 17 | Effect of alkali metal impurities on the low temperature thermal stability of 2090 Al-Cu-Li alloys显示文摘 | Kerr M J Sweet E D Bennett C G | 1996 | Mater Forum1996，21，7222： | 1 |
| 18 | Modeling heterogeneity in a low-permeability gas reservoir using geostatistical techniques, Hyde field, Southern North Sea显示文摘 | SWEET M L BLEWDEN C J CARTER A M | 1996 | AAPG Bulletin1996，80，11： | 1 |
| 19 | Sonochemical production of inter - metallic coatings in heterogeneous media 显示文摘 | Ca sadonte D J Sweet J D | 1994 | Ultrasonics1994，32，6： | 1 |
| 20 | Parkinson' s disease and megacolon: concentric hyaline inclusions(Lewy bodies) in enteric ganglion ceils显示文摘 | Kupsky W J Grimes M M Sweeting J | 1987 | Neurology1987，37，： | 1 |
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