Publications by authors named "Yuyang Fu"

17 Publications

  • Page 1 of 1

Role of formic receptors in soluble urokinase receptor-induced human vascular smooth muscle migration.

J Surg Res 2015 May 12;195(2):396-405. Epub 2015 Feb 12.

Vascular Biology and Therapeutics Program, Houston Methodist Research Institute, Houston, Texas. Electronic address:

Background: Vascular smooth muscle cell (VSMC) migration in response to urokinase is dependent on binding of the urokinase molecule to the urokinase plasminogen receptor (uPAR) and cleavage of the receptor. The aim of this study was to examine the role of the soluble uPAR (suPAR) in VSMC migration.

Methods: Human VSMCs were cultured in vitro. Linear wound and Boyden microchemotaxis assays of migration were performed in the presence of suPAR. Inhibitors to G-protein signaling and kinase activation were used to study these pathways. Assays were performed for mitogen-activated protein kinase and epidermal growth factor receptor activation.

Results: suPAR induced concentration-dependent migration of VSMC, which was G protein-dependent and was blocked by Gαi and Gβγ inhibitors. Removal of the full uPAR molecule by incubation of the cells with a phospholipase did not interfere with this response. suPAR induced ERK1/2, p38(MAPK), and c-Jun N-terminal kinase [JNK] activation in a Gαi/Gβγ-dependent manner, and interruption of these signaling pathways prevented suPAR-mediated migration. suPAR activity was independent of plasmin activity. suPAR did not activate epidermal growth factor receptor. Interruption of the low affinity N-formyl-Met-Leu-Phe receptor (FPRL1) but not high affinity N-formyl-Met-Leu-Phe receptor (FPR) prevented cell migration and activation in response to suPAR. suPAR increased matrix metalloproteinase-2 expression and activity, and this was dependent on the low affinity N-formyl-Met-Leu-Phe receptor (FPRL1) and ERK1/2.

Conclusions: suPAR induces human smooth muscle cell activation and migration independent of the full uPAR through activation of the G protein-coupled receptor FPRL1, which is not linked to the plasminogen activation cascade.
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http://dx.doi.org/10.1016/j.jss.2015.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417467PMC
May 2015

Protease-mediated human smooth muscle cell proliferation by urokinase requires epidermal growth factor receptor transactivation by triple membrane signaling.

J Surg Res 2014 Dec 2;192(2):254-62. Epub 2014 Jul 2.

Vascular Biology and Therapeutics Program, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas; Department of Cardiovascular Surgery, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas. Electronic address:

Background: Urokinase (uPA) modulates cellular and extracellular matrix responses within the microenvironment of the vessel wall and has been shown to activate the epidermal growth factor receptor (EGFR). This study examines the role of the protease domain of uPA during EGFR activation in human vascular smooth muscle cells (VSMC).

Methods: Human coronary VSMC were cultured in vitro. Assays of cell proliferation and EGFR phosphorylation were examined in response to the carboxyterminal fragment of uPA (CTF) in the presence and absence of the plasmin, metalloprotease and a disintegrin and metalloproteinase (ADAM) inhibitors, heparin-bound epidermal growth factor (HB-EGF), and EGFR inhibitors, and small interfering RNA to EGFR and ADAMs.

Results: CTF produced a dose-dependent increase in DNA synthesis and cell proliferation in human VSMC, which was blocked in a dose-dependent manner by both plasmin inhibitors and the EGFR inhibitor, AG1478. CTF induced time-dependent EGFR phosphorylation, which was blocked by inhibitors of plasmin and metalloproteinases activity. The presence of urokinase plasminogen activator receptor was not required. Inhibition of ADAM-10 and -12, and of HB-EGF blocked EGFR activation in response to CTF. CTF-mediated activation of EGFR was mediated through Gβγ, src, and NAD(P)H oxidase.

Conclusions: In human coronary VSMC, uPA induces uPAR-independent, domain-dependent smooth muscle cell proliferation through transactivation of EGFR by a plasmin-mediated, ADAM-induced, and HB-EGF-dependent process, which is mediated by the intracellular pathways involving Gαi, Gβγ, src, and NAD(P)H oxidase.
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http://dx.doi.org/10.1016/j.jss.2014.06.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252843PMC
December 2014

Effect of metabolic syndrome on the response to arterial injury.

J Surg Res 2014 Sep 27;191(1):33-41. Epub 2014 May 27.

Vascular Biology and Therapeutics Program, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas; Department of Cardiovascular Surgery, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas. Electronic address:

Background: Metabolic syndrome is now an epidemic in the United States population. Intimal hyperplasia remains the principal lesion in the development of restenosis after vessel wall injury. The aim of this study is to characterize the changes induced in wall morphology in the developing intimal hyperplasia within a murine model in the presence of diabetes (type 1) and metabolic syndrome.

Methods: Control (wild type B6), Non Obese Diabetic, and metabolic syndrome (RCS-10) mice were used. The murine femoral wire injury model was used in which a micro wire is passed through a branch of the femoral and used to denude the common femoral and iliac arteries. Specimens were perfusion fixed and sections were stained with hematoxylin and eosin and Movat stains such that dimensional and compositional morphometry could be performed using an ImagePro system. Additional stains for proliferation and apoptosis were used.

Results: In control mice, the injured femoral arteries develop intimal hyperplasia, which is maximal at 28 d and remains stable to day 56. Sham-operated vessels do not produce such a response. In diabetic mice, the intimal response increased 5-fold with a 2-fold increase in proteoglycan deposition, whereas in the metabolic syndrome mice there was a 6-fold increase in the intimal response and a similar increase in proteoglycan deposition. Collagen deposition was different with a 22-fold increase over control in collagen deposition in diabetes and a 100-fold increase over control in collagen deposition in metabolic syndrome as compared with the control injury mice. Maximal vascular smooth muscle cell (VSMC) proliferation was decreased in both diabetes and metabolic syndrome compared with controls, whereas early cell apoptosis in both diabetes and metabolic syndrome was sustained over a longer period of time compared with wild-type mice.

Conclusions: These data demonstrate that development of intimal hyperplasia is markedly different in diabetes and metabolic syndrome compared with controls, with an increase in collagen deposition, a reduction in VSMC proliferation, and an increase in early VSMC apoptosis. These findings suggest that preventative strategies against restenosis must be tailored for the diabetic and metabolic syndrome patients.
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http://dx.doi.org/10.1016/j.jss.2014.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134773PMC
September 2014

Gαq G proteins modulate MMP-9 gelatinase during remodeling of the murine femoral artery.

J Surg Res 2013 May 8;181(1):32-40. Epub 2012 May 8.

Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, Houston, Texas.

Background: Vessels heal after injury and G protein-coupled receptors are involved in the vascular smooth muscle cell proliferation required to form intimal hyperplasia. We have previously identified the role of Gαq in vascular smooth muscle cell proliferation in vitro. This study now examines the role of Gαq in the developing intimal hyperplasia in a murine model and the impact of disruption of Gαq signaling on intimal hyperplasia development.

Methods: We employed a murine femoral wire injury model in which a micro-wire is passed through a branch of the femoral artery and used to denude the common femoral artery. We perfusion-fixed specimens and stained sections with hematoxylin-eosin and Movat's stains such that morphometric analysis could be performed using an Image-Pro system. We also harvested additional specimens of femoral artery and snap-froze them for Western blotting or zymography, to allow for the study of G protein expression and both protease expression and activity. We used contralateral vessels as controls. We immersed additional vessels in pluronic gel containing the chemical Gαq G protein inhibitors GP-2A, siRNA to Gαq or adenovirus containing mutant inactive Gαq.

Results: Gαq expression increased in a time-dependent manner after femoral artery injury. Sham-operated vessels did not produce such a response. Inhibition of Gαq reduced cell proliferation without affecting cell migration. Interruption of Gαq signaling also inhibited the development of intimal hyperplasia. Inhibition of Gαq did not alter peak urinary-type plasminogen activator activity and expression, but did increase early plasminogen activator inhibitor-1 activity and expression. Inhibition of Gαq reduced peak metalloproteinase (MMP)-9 activity at Day 3 but did not influence peak MMP-2 activity at Day 7. Protein expression for MMP-9 was also decreased, but that of MMP-2 was not affected. There were no changes in the expression or the activity of the respective inhibitors for MMP-9 and MMP-2, and tissue inhibitor of metalloproteinases-1 and -2.

Conclusions: These data demonstrate that femoral wire injury in the mouse is associated with a time-dependent increase in Gαq expression. Inhibition of Gαq alters cell proliferation and is associated with decreased MMP-9 expression and activity.
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http://dx.doi.org/10.1016/j.jss.2012.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424329PMC
May 2013

Urokinase requires NAD(P)H oxidase to transactivate the epidermal growth factor receptor.

Surgery 2012 Nov 8;152(5):879-85. Epub 2012 May 8.

Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, Houston, TX, USA.

Background: Cell migration is an integral part of the development of intimal hyperplasia, and proteases are pivotal components in the process. Cell migration in response to urokinase is mediated through the aminoterminal fragment (ATF) of the protein. This study examines the role of NAD(P)H oxidase during epidermal growth factor receptor (EGFR) transactivation by ATF in human vascular smooth muscle cells (VSMC).

Methods: Human VSMCs were cultured in vitro. Linear wound and Boyden microchemotaxis assays of migration in response to ATF were performed in the presence and absence of NAD(P)H oxidase inhibitors (diphenyleneiodonium [DPI] and apocynin) and small interfering RNA (siRNA) to Nox1. Additional assays were performed to examine the upstream pathways that lead to NAD(P)H oxidase activity. Assays were also performed for EGFR activation.

Results: ATF produced concentration-dependent VSMC migration, which was inhibited by increasing concentrations of DPI and apocynin. ATF was shown to induce time-dependent EGFR phosphorylation, which peaked at 4-fold greater than control. This response was inhibited by DPI and apocynin in a concentration-dependent manner. ATF induced a concentration-dependent increase in intracellular oxygen free radical species, which was mitigated by the presence of DPI and apocynin. Inhibition of Gβγ by βARK(CT) reduced both NAD(P)H oxidase activity and EGFR activation. Inhibition of rac, which allows the NAD(P)H complex to assemble on the membrane, and inhibition of src, which induces assembly of the complex, both reduced ATF-dependent NAD(P)H oxidase activity and EGFR phosphorylation. siRNA to Nox1 prevented ATF-mediated EGFR activation and cell migration.

Conclusion: ATF requires NAD(P)H oxidase activity through a Gβγ-, rac-, and src-mediated pathway to facilitate transactivation of EGFR and VSMC migration.
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http://dx.doi.org/10.1016/j.surg.2012.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419340PMC
November 2012

Role of S-1-P receptors and human vascular smooth muscle cell migration in diabetes and metabolic syndrome.

J Surg Res 2012 Oct 11;177(2):e75-82. Epub 2012 Mar 11.

Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, Houston, TX, USA.

Background: Sphingosine-1-phosphate (S-1-P) is a bioactive sphingolipid released from activated platelets that stimulates migration of vascular smooth muscle cells (VSMC) in vitro. S-1-P is associated with oxidized low-density lipoprotein (oxLDL) and is important in vessel remodeling. S-1-P will activate multiple G protein-coupled receptors (S-1-PR 1 to 5), which can regulate multiple cellular functions, including cell migration. The aim of this study is to examine the role of S-1-PR signaling during smooth muscle cell migration in response to S-1-P.

Methods: Human VSMCs were cultured in vitro. Expression of S-1-PR 1 to 5 was determined in conditions mirroring diabetes (40 mM glucose) and metabolic syndrome (25 mM glucose with 20 μM linoleic acid and 20 μM oleic acid). Linear wound and Boyden microchemotaxis assays of migration were performed in the presence of S-1-P with and without siRNA against S-1-PR 1 to 5. Assays were performed for activation of ERK1/2, p38(MAPK) and JNK.

Results: Human VSMCs express S-1-PR1, S-1-PR2, and S-1-PR3. There was no significant expression of S-1-PR4 and S-1-PR5. The expression of S-1-PR1 and S-1-PR3 is enhanced under high glucose conditions and metabolic syndrome conditions. Migration of VSMC in response to S-1-P is enhanced 2-fold by diabetes and 4-fold by metabolic syndrome. In diabetes, S-1-PR1 expression is enhanced, while S-1-PR2 and S-1-PR3 expression are both maintained. In metabolic syndrome, S-1-PR1 and 3 expressions are enhanced and that of S-1-PR2 is reduced. siRNA to S-1-PR1 results in a 2-fold reduction in S-1-P-mediated cell migration under all conditions. siRNA to S-1-PR2 enhanced cell migration only under normal conditions, while siRNA S-1-PR3 decreased migration in metabolic syndrome only. Down-regulation of S-1-PR1 reduced ERK1/2 activation in response to S-1-P, while that of S-1-PR2 had no effect under normal conditions. In diabetes, down-regulation of S-1-PR1 reduced activation of all three MAPKs. In metabolic syndrome, down-regulation of S-1-PR1 and S-1-PR3 reduced activation of all three MAPKs.

Conclusion: S-1-PR 1, 2, and 3 regulate human VSMC migration and their expression level and function are modulated by conditions simulating diabetes and metabolic syndrome.
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http://dx.doi.org/10.1016/j.jss.2011.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392410PMC
October 2012

Peritoneal catheter implantation elicits IL-10-producing immune-suppressor macrophages through a MyD88-dependent pathway.

Clin Immunol 2012 Apr 17;143(1):59-72. Epub 2012 Jan 17.

Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.

Catheters are implanted into the peritoneal cavity during the process of peritoneal dialysis. Though these catheters may be effective and beneficial, the impact of catheters on the immune system is poorly understood. Catheters and other devices implanted in the peritoneal cavity elicit a foreign body reaction. However, the immunological consequences of this remain uncharacterized. To model this, catheters were implanted into the peritoneal cavity of healthy mice. Catheter implantation induced rapid cellular changes within the peritoneal cavity. Whereas B-cells and T-cells were reduced, catheter implantation was associated with the rapid expansion of F4/80-low-positive, CD11b-positive macrophages that elaborated IL-10, and suppressed T-cell division and Th1 skewing in co-culture assays. Peritoneal catheter elicited macrophages had increased Jmjd3 but reduced NF-κB activation, and their emergence was MyD88-dependent. Collectively, these studies indicate that foreign body implantation into the peritoneal cavity is associated with the expansion of suppressor macrophages. Whether peritoneal cavity catheter implantation may have systemic immunoregulatory roles remains to be explored.
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http://dx.doi.org/10.1016/j.clim.2012.01.003DOI Listing
April 2012

Role for Gβγ G-proteins in protease regulation during remodeling of the murine femoral artery.

J Surg Res 2012 Nov 5;178(1):40-7. Epub 2011 Sep 5.

Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, and Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, The Methodist Hospital, Houston, Texas 77030, USA.

Background: Intimal hyperplasia remains the principal lesion in the development of restenosis after vessel wall injury. G-protein coupled receptors are involved in smooth muscle cell proliferation but the role of Gβγ in arterial intimal hyperplasia has not been well defined. The aim of this study is to characterize the expression of Gβγ G-proteins in the developing intimal hyperplasia in a murine model and the impact of disruption of Gβγ signaling on intimal hyperplasia development.

Methods: The murine femoral wire injury model was employed. Specimens were perfusion-fixed and sections were stained with H&E and Movat's stains such that morphometry could be performed using an Image-Pro system. Additional specimens of femoral artery were also harvested and snap frozen for Western blotting for the Gβγ expression and for Western blotting and zymography to allow for the study of gelatinase and plasminogen activator expression and activation. Contralateral vessels were used as controls. Additional vessels were immersed in pluronic gel containing an adenovirus with the Gβγ inhibitor βARK(CT).

Results: The injured femoral arteries developed intimal hyperplasia, while sham vessels did not produce such a response. Cell proliferation peaked at 3-5 d and cell migration at 7 d after injury. There was a marked time-dependent increase in Gβγ over the 28 d following injury. Inhibition of Gβγ with βARK(CT) inhibited cell proliferation, cell migration and the development of intimal hyperplasia. Inhibition of Gβγ decreased peak uPA activity and expression without increasing early PAI-1 activity and expression. Inhibition of Gβγ reduced peak MMP-2 activity at d 1 but not at d 7 and also reduced peak MMP-9 activity at d 3. Protein expression for both MMP-2 and MMP-9 was also transiently decreased. There were no changes in TIMP-1 and TIMP-2 expression and activity.

Conclusions: These data demonstrate a time-dependent increase in Gβγ G-protein expression following wire injury in the mouse. Inhibition of Gβγ alters cell proliferation and migration with associated changes in MMP-2, MMP-9, and uPA expression and activity.
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http://dx.doi.org/10.1016/j.jss.2011.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251654PMC
November 2012

SRC regulates sphingosine-1-phosphate mediated smooth muscle cell migration.

J Surg Res 2012 Jun 10;175(1):30-4. Epub 2011 Aug 10.

Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, Houston, Texas 77030, USA.

Background: Sphingosine-1-phosphate (S-1-P) is a bioactive sphingolipid released from activated platelets at sites of arterial injury that stimulates migration of smooth muscle cells (SMC). The kinase src is a significant focal point in transmembrane signaling. This study examines the role of src during smooth muscle cell migration in response to S-1-P.

Methods: Human coronary arterial SMCs were cultured in vitro. Boyden microchemotaxis assays of migration were performed in response to S-1-P in the presence and absence the src inhibitor (PP2, 10 μM) and a dominant negative src construct (DNsrc). siRNA to S-1-P receptors was used to down-regulate the S-1-P receptors. Western blotting was performed for src and MAPK phosphorylation.

Results: Inhibition of src with PP2 but not PP3 partially blocked S-1-P-mediated cell migration. S-1-P induced time-dependent activation of src, which was inhibited by PP2 and adenoviral DNsrc. PP3 or an empty vector had no effect. Activation of src by S-1-P was inhibited by siRNA to S-1-PR1 and S-1-PR3 but not by S-1-PR2. When the VSMC were transfected with adenovirus containing βARK(CT), an inhibitor to Gβγ, src activation was significantly attenuated. Src inhibition with PP2 reduced p38(MAPK) and JNK activation but did not alter ERK1/2 activation.

Conclusion: S-1-P mediated VSMC migration is modulated by a G-protein-coupled src pathway partially through src-mediated p38(MAPK) and JNK signaling and requires S-1-PR1 and S-1-PR3 receptors.
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http://dx.doi.org/10.1016/j.jss.2011.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242881PMC
June 2012

RANTES deficiency attenuates autoantibody-induced glomerulonephritis.

J Clin Immunol 2011 Feb 1;31(1):128-35. Epub 2010 Oct 1.

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Mail Code 8884, Y8.212, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA.

Experimental autoimmune nephritis in mice and spontaneous lupus nephritis are both associated with elevated expression of several chemokines in the kidneys. Nevertheless, the role that different chemokines play in mediating renal inflammation is far from complete. This study focuses on elucidating the functional role of RANTES, a chemokine that has been noted to be hyper-expressed within the kidneys, both in experimental renal disease as well as in spontaneous lupus nephritis. To elucidate if RANTES was essential for immune-mediated glomerulonephritis, DBA/1 mice that are highly sensitive to nephrotoxic serum nephritis were rendered RANTES-deficient and then tested for disease susceptibility. Nephritis-sensitive DBA/1 mice expressed more RANTES within the diseased kidneys. Compared to wild-type DBA/1 mice, RANTES-deficient DBA/1 mice developed significantly less proteinuria, azotemia, and renal inflammation, with reduced crescent formation and tubulo-interstitial nephritis. These findings indicate that RANTES ablation attenuates immune-mediated nephritis and suggest that this chemokine could be a potential therapeutic target in these diseases.
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http://dx.doi.org/10.1007/s10875-010-9470-xDOI Listing
February 2011

Urine proteome scans uncover total urinary protease, prostaglandin D synthase, serum amyloid P, and superoxide dismutase as potential markers of lupus nephritis.

J Immunol 2010 Feb 11;184(4):2183-93. Epub 2010 Jan 11.

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75235, USA.

To identify potential biomarkers in immune-mediated nephritis, urine from mice subjected to an augmented passive model of anti-glomerular basement membrane (GBM)-induced experimental nephritis was resolved using two-dimensional gels. The urinary proteome in these diseased mice was comprised of at least 71 different proteins. Using orthogonal assays, several of these molecules, including serum amyloid P (SAP), PG D synthase, superoxide dismutase, renin, and total protease were validated to be elevated in the urine and kidneys of mice during anti-GBM disease, as well as in mice with spontaneously arising lupus nephritis. Among these, urinary protease was the only marker that appeared to be exclusively renal in origin, whereas the others were partly serum-derived. Longitudinal studies in murine lupus demonstrated that total urinary protease had better predictive value for histologically active nephritis (r = 0.78) compared with proteinuria (r = -0.04), azotemia (r = 0.28), or the other markers examined, whereas urine SAP emerged as the single most predictive marker of histological glomerulonephritis. Collectively, these studies uncover total urinary protease, PG D synthase, SAP, and superoxide dismutase as novel biomarkers of anti-GBM disease and lupus nephritis, with stronger correlation to renal disease compared with currently employed biomarkers. These findings could have important diagnostic and prognostic ramifications in the management of these renal diatheses.
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http://dx.doi.org/10.4049/jimmunol.0900292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927858PMC
February 2010

Type I interferons produced by resident renal cells may promote end-organ disease in autoantibody-mediated glomerulonephritis.

J Immunol 2009 Nov 28;183(10):6831-8. Epub 2009 Oct 28.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.

Increased Type I IFNs or IFN-I have been associated with human systemic lupus erythematosus. Interestingly augmenting or negating IFN-I activity in murine lupus not only modulates systemic autoimmunity, but also impacts lupus nephritis, suggesting that IFN-I may be acting at the level of the end-organ. We find resident renal cells to be a dominant source of IFN-I in an experimental model of autoantibody-induced nephritis. In this model, augmenting IFN-I amplified antibody-triggered nephritis, whereas ablating IFN-I activity ameliorated disease. One mechanism through which increased IFN-I drives immune-mediated nephritis might be operative through increased recruitment of inflammatory monocytes and neutrophils, though this hypothesis needs further validation. Collectively, these studies indicate that an important contribution of IFN-I toward the disease pathology seen in systemic autoimmunity may be exercised at the level of the end-organ.
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http://dx.doi.org/10.4049/jimmunol.0900742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876821PMC
November 2009

Experimental anti-GBM nephritis as an analytical tool for studying spontaneous lupus nephritis.

Arch Immunol Ther Exp (Warsz) 2008 Jan-Feb;56(1):31-40. Epub 2008 Feb 5.

Department of Internal Medicine/Rheumatology and Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in immune-mediated damage to multiple organs. Among these, kidney involvement is the most common and fatal. Spontaneous lupus nephritis (SLN) in mouse models has provided valuable insights into the underlying mechanisms of human lupus nephritis. However, SLN in mouse models takes 6-12 months to manifest; hence there is clearly the need for a mouse model that can be used to unveil the pathogenic processes that lead to immune nephritis over a shorter time frame. In this article more than 25 different molecules are reviewed that have been studied both in the anti-glomerular basement membrane (anti-GBM) model and in SLN and it was found that these molecules influence both diseases in a parallel fashion, suggesting that the two disease settings share common molecular mechanisms. Based on these observations, the authors believe the experimental anti-GBM disease model might be one of the best tools currently available for uncovering the downstream molecular mechanisms leading to SLN.
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http://dx.doi.org/10.1007/s00005-008-0007-4DOI Listing
May 2008

Experimental anti-GBM disease as a tool for studying spontaneous lupus nephritis.

Clin Immunol 2007 Aug;124(2):109-18

Department of Internal Medicine (Rheumatology) and Immunology, University of Texas Southwestern Medical School, Y8.204, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA.

Lupus nephritis is an immune-mediated disease, where antibodies and T cells both play pathogenic roles. Since spontaneous lupus nephritis in mouse models takes 6-12 months to manifest, there is an urgent need for a mouse model that can be used to delineate the pathogenic processes that lead to immune nephritis, over a quicker time frame. We propose that the experimental anti-glomerular basement membrane (GBM) disease model might be a suitable tool for uncovering some of the molecular steps underlying lupus nephritis. This article reviews the current evidence that supports the use of the experimental anti-GBM nephritis model for studying spontaneous lupus nephritis. Importantly, out of about 25 different molecules that have been specifically examined in the experimental anti-GBM model and also spontaneous lupus nephritis, all influence both diseases concordantly, suggesting that the experimental model might be a useful tool for unraveling the molecular basis of spontaneous lupus nephritis. This has important clinical implications, both from the perspective of genetic susceptibility as well as clinical therapeutics.
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http://dx.doi.org/10.1016/j.clim.2007.05.007DOI Listing
August 2007

Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-alpha production.

J Immunol 2006 Jan;176(1):632-9

Division of Rheumatology, and Center for Immunology, University of Southwestern Medical Center, Dallas, TX 75390, USA.

Innate stimuli are well recognized as adjuvants of the systemic immune response. However, their role in driving end-organ disease is less well understood. Whereas the passive transfer of glomerular-targeting Abs alone elicited minimal renal disease, the concomitant delivery of innate stimuli triggered severe nephritis, characterized by proliferative glomerulonephritis with crescent formation, and tubulointerstitial disease. Specifically, stimulating TLR2, TLR3, TLR4, and TLR5 by using peptidoglycan, poly(I:C), LPS, and flagellin, respectively, all could facilitate anti-glomerular Ab-elicited nephritis. In this model, innate and immune triggers synergistically activated several cytokines and chemokines, including IL-1, IL-6, TNF-alpha, and MCP-1, some of which were demonstrated to be absolutely essential for the development of renal disease. Genetic studies revealed that, whereas the innate trigger is dependent on TLR/IL-1R-associated kinase-mediated signaling, the immune component was contingent on FcR-mediated signals. Importantly, infiltrating leukocytes as well as intrinsic glomerular cells may both serve to integrate these diverse signals. Extrapolating to spontaneous immune-mediated nephritis, although the adaptive immune system may be important in generating end-organ targeting Abs, the extent of damage inflicted by these Abs may be heavily dependent on cues from the innate immune system.
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http://dx.doi.org/10.4049/jimmunol.176.1.632DOI Listing
January 2006

The lipopolysaccharide-triggered mesangial transcriptome: Evaluating the role of interferon regulatory factor-1.

Kidney Int 2005 Apr;67(4):1350-61

Simmons Arthritis Research Center, Division of Rheumatology, Center for Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Presently, we do not have a clear picture of how the mesangial transcriptome evolves following stimulation. The present study was designed to address this, using an innate trigger to stimulate murine mesangial cells.

Methods: Three independent mesangial cell lines derived from C57BL/6 mice were stimulated with lipopolysaccharide (LPS). The mesangial cell transcriptomes were defined 1, 6, 24, and 60 hours poststimulation with LPS, using a 17,000 gene oligonucleotide array.

Results: Interferon regulatory factor-1 (IRF-1), ScyA2/MCP1, ScyA20/MIP3alpha (ScyB1/Gro1, and ScyB2/MIP2alpha/Gro2 were the earliest genes to be hyperexpressed after LPS stimulation. Later-appearing genes included ScyA7/MCP3, ScyD1/fractalkine, GM-CSF/CSF-2, PDGF, epiregulin, NfKb, C/EBP, TIMP-1, MMP11, MMP13, PTGS2/COX2, SpI2-1, Spp1, PAI-1, VCAM-1, C3, and defensin-beta1, among others. Several of these changes were validated by real-time polymerase chain reaction (PCR) or enzyme-linked immunosorbent assay (ELISA). Rapid IRF-1 hyperexpression was also noted following stimulation of mesangial cells with peptidoglycan, poly I:poly C, interferon-gamma?(IFN-gamma), and heat-aggregated IgG. However, the blocking of IRF-1 using RNA interference and the use of mesangial cells isolated from IRF-1-deficient mice could not substantiate an obligatory role for IRF-1 in LPS-induced mesangial cell activation. Likewise, IRF-1 deficiency did not impact the development of anti-glomerular basement membrane (GBM)-induced immune nephritis.

Conclusion: Innate stimuli such as LPS appear to trigger successive waves of mesangial cell gene expression. Although IRF-1 surfaces as an "early-on, early-off" transcription factor following several different triggers, it does not appear to be an essential molecule for mesangial cell activation by innate triggers or for anti-GBM disease.
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http://dx.doi.org/10.1111/j.1523-1755.2005.00212.xDOI Listing
April 2005

Liver transplantation at the Sun Yat-Sen University of Medical Sciences in China.

Chin Med J (Engl) 2002 Apr;115(4):543-8

Transplantation Center, The First Affiliated Hospital of Sun Yat-Sen University of Medical Sciences, Guangzhou 510080, China.

Objectives: To summarize the results of liver transplantation for various end-stage liver diseases at the Sun Yat-Sen University of Medical Sciences (SUMS), define the role of liver transplantation in the treatment of hepatocellular carcinoma and fulminant hepatitis B, and assess the efficiency of lamivudine on preventing HBV recurrence.

Methods: Seventy liver transplants performed at the SUMS between April 1993 and December 2000 were retrospectively analyzed. The main indications for liver transplant were hepatocellular carcinoma (26 cases), liver cirrhosis (21 cases), fulminant hepatitis B (12 cases), sclerosing cholangitis (4 cases) and other terminal liver diseases (7 cases). Lamivudine was used in twelve patients suffering from fulminant hepatitis B. Logistic multivariate regression analysis was applied to determine the risk factors predicting liver transplantation outcomes.

Results: Fifty-four patients survived for more than one month, and 16 patients died within 30 days after orthotopic liver transplantation (OLT). The overall hospital survival rate was 77.1%. The hospital survival rates in the Child's A and B patients were 87.5% and 83.3%, respectively. Those rates were superior to those of the Child's C patients (P < 0.05). The outcome of patients with small hepatocellular carcinoma (HCC) was superior to that of patients with large HCC. Preoperative APACE III scores, the severity of ascites and serum creatine level had independent influence on outcome. Of the patients with fulminant HBV infection, 9 recipients survived for a follow-up period of 2 - 24 months. Treatment with lamivudine monotherapy was both well tolerated and efficacious in patients with fulminant hepatitis B.

Conclusions: The results indicate that orthotopic liver transplantation could provide long-term cure and palliation for patients with HCC, and that patient selection is extremely important in predicting outcome. The results support the continued application of liver transplantation as a therapeutic modality for various end-stage liver diseases and that lamivudine is an effective and safe monotherapy in OLT for patients with HBV infection.
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April 2002