|
1
|
Ghanima W, Boiocchi L, Lee CS, Feng X, Geyer JT, Gudbrandsdottir S, Orazi A, Junker P, Bussel JB. Immune thrombocytopenia is associated with persistently deranged fibrosis-related seromarker profiles but low bone marrow fibrosis grades: A 2-year observational study on thrombopoietin receptor agonist treatment. Platelets 2018; 30:222-228. [PMID: 29293383 DOI: 10.1080/09537104.2017.1411586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/22/2017] [Accepted: 11/26/2017] [Indexed: 10/18/2022]
Abstract
Bone marrow (BM) fibrosis is a potential side effect of thrombopoietin receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment. Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years. BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of PIIINP, PINP, ICTP, and HYA were significantly increased in ITP versus controls. PINP, PIIINP, and HYA decreased on TPO-RA; ICTP remained unchanged. PINP:ICTP was lower before and during treatment compared to controls. Pretreatment, TGF-beta was lower than in controls; HGF exhibited the opposite pattern. HYA, ICTP, and TGF-beta tended to increase while PINP and platelet-derived growth factor tended to decrease with increasing fibrosis grade. In conclusion, ITP is associated with deranged patterns of extracellular matrix seromarkers and growth factors, indicating that BM stromal remodeling is enhanced. During TPO-RA treatment for up to 2 years, this profile was partially reversed while mild BM reticulin fibrosis was still present in the majority of patients. These observations likely reflect a BM injury by autoimmunity that is modified by TPO-RA.
Collapse
Affiliation(s)
- Waleed Ghanima
- a Departments of Research , Medicine and Oncology, Østfold Hospital Trust, Grålum, Norway
- b Departments of Hematology, Institute of clinical medicine , Oslo University , Oslo Norway
| | - Leonardo Boiocchi
- c Pathology Department , Massachusetts General Hospital , Boston , MA , USA
| | - Christina S Lee
- d Department of Pediatrics, Division of Hematology/Oncology , Weill Cornell Medical College , New York, NY , USA
| | - Xingmin Feng
- e National Heart, Lung, and Blood Institute , NIH , Bethesda , MD , USA
| | - Julia Turbiner Geyer
- f Department of Pathology and Laboratory Medicine , Weill Cornell Medical College , New York , NY , USA
| | - Sif Gudbrandsdottir
- g Department of Haematology , Copenhagen University Hospital Roskilde , Roskilde, Denmark
| | - Attilio Orazi
- f Department of Pathology and Laboratory Medicine , Weill Cornell Medical College , New York , NY , USA
| | - Peter Junker
- h Department of Rheumatology C , Odense University Hospital and Institute of Clinical Research, University of Southern Denmark , Odense, Denmark
| | - James B Bussel
- d Department of Pediatrics, Division of Hematology/Oncology , Weill Cornell Medical College , New York, NY , USA
| |
Collapse
|
|
2
|
Nakanishi C, Doi H, Katsura K, Satomi S. Treatment with L-Valine Ameliorates Liver Fibrosis and Restores Thrombopoiesis in Rats Exposed to Carbon Tetrachloride. TOHOKU J EXP MED 2010; 221:151-9. [DOI: 10.1620/tjem.221.151] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Chikashi Nakanishi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University
| | - Hideyuki Doi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University
| | - Kazunori Katsura
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University
| | - Susumu Satomi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University
| |
Collapse
|
|
3
|
Abstract
Hepatocyte growth factor (HGF), originally purified from the plasma of patients with fulminant hepatic failure, has been shown to carry out various physiological functions. HGF not only stimulates liver regeneration, but also acts as an antiapoptotic factor in in vivo experimental models. Therefore, HGF is a promising therapeutic agent for the treatment of fatal liver diseases, including fulminant hepatic failure. After performing a number of preclinical tests, our group began an investigator-initiated registered phase I/II clinical trial of patients with fulminant hepatic failure to examine the safety and clinical efficacy of recombinant human HGF. In this article, we will discuss the basic research results as well as the translational research that underpins current attempts to use HGF in various clinical settings.
Collapse
Affiliation(s)
- Akio Ido
- Department of Digestive and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan
| | | |
Collapse
|
|
4
|
Abstract
OBJECTIVE The liver is the primary site of hematopoiesis during fetal development; it has been shown that thrombopoietin (TPO) produced by the liver during fetal development is a major regulator of megakaryocytopoiesis. As maximum liver growth and hematopoiesis occur simultaneously, we hypothesized that TPO may act as a growth factor for hepatic progenitors. Therefore, the influence of TPO on the proliferation of fetal hepatic progenitors in vitro compared with that of adult hepatocytes was analyzed. The expression of the TPO receptor, c-mpl, was investigated in fetal and adult liver. METHODS Cell proliferation was measured by bromodeoxyuridine incorporation and total cell counts. TPO and c-mpl gene expression was investigated by reverse transcription polymerase chain reaction. The cell surface expression of c-mpl was analyzed in fetal and adult human liver by immunohistochemistry. RESULTS Hepatic progenitors of fetal and adult liver but not hepatocytes expressed the TPO receptor, c-mpl, on the cell surface. Fetal hepatic progenitors expressed mRNA for TPO and its receptor. TPO stimulated cell proliferation and increased cell numbers of cultured rat fetal hepatic progenitors but not adult hepatocytes. CONCLUSION We conclude that TPO acts in addition to its known role in megakaryocytopoiesis as a growth factor for hepatic progenitors but not hepatocytes in vitro; thus, TPO represents a growth factor for hepatic progenitors during fetal liver development.
Collapse
|
|
5
|
Shackel NA. Growth factors as indicators of prognosis in liver failure. J Gastroenterol Hepatol 2007; 22:1171-3. [PMID: 17688658 DOI: 10.1111/j.1440-1746.2007.05005.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
|
|
6
|
Sugiura K, Taketani S, Yoshimura T, Nishino T, Nishino N, Fujisawa JI, Hisha H, Inaba T, Ikehara S. Effect of hepatocyte growth factor on long term hematopoiesis of human progenitor cells in transgenic-sever combined immunodeficiency mice. Cytokine 2007; 37:218-26. [PMID: 17512212 DOI: 10.1016/j.cyto.2007.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2006] [Revised: 03/01/2007] [Accepted: 04/02/2007] [Indexed: 11/18/2022]
Abstract
Hepatocyte growth factor (HGF), which was originally isolated as a liver generating factor, enhances hematopoiesis. To study the effect of HGF on hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs), we generated severe combined immunodeficiency (SCID) mice producing human (h) HGF and/or stem cell factor (SCF) by transferring the relevant genes to fertilized eggs, and then transplanted hematopoietic progenitors from human cord blood into the transgenic (Tg) SCID mice. Six months after transplantation, a significantly larger number of human cells were found in the Tg SCID mice than in non-Tg controls. Characteristically, the recipient SCID mice producing h HGF (HGF-SCID) had a significantly increased number of h CD41+ cells, whereas the SCF-SCID recipients had more CD11b+ cells. Significantly large numbers of CD34+ progenitors were found in the SCID mice transferred with both h HGF and h SCF genes (HGF/SCF-SCID) when compared with HGF-SCID or SCF-SCID mice. These results imply that HGF supports the differentiation of progenitors in megakaryocyte lineage, whereas SCF supports that in myeloid lineage. The results also imply that HGF acts on HSCs/HPCs as a synergistic proliferative factor combined with SCF. We have demonstrated the advantage of the human cytokine-producing animal in the maintenance of human HSCs.
Collapse
Affiliation(s)
- Kikuya Sugiura
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai City, Osaka, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Kosone T, Takagi H, Horiguchi N, Toyoda M, Sohara N, Kakizaki S, Sato K, Nishiyama U, Kuwaki T, Mori M. Hepatocyte growth factor accelerates thrombopoiesis in transgenic mice. J Transl Med 2007; 87:284-291. [PMID: 17260004 DOI: 10.1038/labinvest.3700514] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hepatocyte growth factor (HGF) is one of the potent growth factors for liver regeneration and has a strong effect on epithelial and nonepithelial cells. As one of the pleiotropic functions, HGF acts as a hematopoietic regulator in the proliferation and differentiation of hematopoietic progenitors. However, the effect of HGF on the thrombopoietic function remains unclear. The correlation between HGF and thrombopoiesis was investigated in transgenic (TG) mice overexpressing murine HGF controlled by the murine HGF by the metallothionein promoter. Furthermore, the mechanism of thrombocytosis induced by HGF in vitro was analyzed in hepatoma cell line HepG2. Both the platelet count and the serum thrombopoietin (TPO) concentration were significantly higher in TG than in the wild type (WT) control mice. In the liver and spleen, the expression of TPOmRNA in TG was higher than that in WT by real-time polymerase chain reaction. The expressions of transcriptional factor of TPO, GABP-alpha/beta were more increased in TG liver compared to WT. In an in vitro study, HGF induced TPO and GABP-alpha/beta expression and enhanced TPO promoter activity. Therefore, HGF induced thrombopoiesis accompanied with the overexpression of TPO through GABP stimulation.
Collapse
Affiliation(s)
- Takashi Kosone
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Reinhold A, Zhang J, Gessner R, Felderhoff-Mueser U, Obladen M, Dame C. High Thrombopoietin Concentrations in The Cerebrospinal Fluid of Neonates with Sepsis And Intraventricular Hemorrhage May Contribute to Brain Damage. J Interferon Cytokine Res 2007; 27:137-45. [PMID: 17316141 DOI: 10.1089/jir.2006.0096] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Thrombopoietin (TPO) and its receptor (TPOR) are expressed in the central nervous system (CNS). Although TPO shares significant homology with various neurotrophins, recent data indicate a proapoptotic function of TPO in the CNS. In this study, TPO concentrations were analyzed in the cerebrospinal fluid (CSF) of neonates. Human neuroblastoma-derived SH-SY5Y cells were established to elucidate the effects of inflammation and hypoxia on neuronal Tpo expression. TPO was detectable in the CSF of 6 of 15 neonates with bacterial infection/sepsis (median 140, range 2-613 pg/mL), 5 of 9 neonates with posthemorrhagic hydrocephalus (median 31, range 1.4-469 pg/mL), 3 of 4 neonates with posthemorrhagic hydrocephalus plus bacterial infection/sepsis or meningitis (median 97, range 6-397 pg/mL), but not in controls ( n = 3). Neither the presence of detectable TPO nor its level in the CSF significantly correlated with any clinical or laboratory parameter. In SH-SY5Y cells, TPO and TPOR expression was detected by RT-PCR and Western blot analysis. In vitro, interleukin-6 (IL-6) did not significantly change Tpo gene expression. In contrast, Tpo mRNA expression significantly decreased under hypoxia, whereas erythropoietin (EPO) mRNA expression increased. In conclusion, our data provide evidence that in neuronal cells, TPO production is regulated by different mechanisms than in hepatocytes.
Collapse
Affiliation(s)
- Anke Reinhold
- Department of Neonatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany
| | | | | | | | | | | |
Collapse
|
|
9
|
|
|
10
|
Abstract
Our understanding of thrombopoiesis--the formation of blood platelets--has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances.
Collapse
Affiliation(s)
- Kenneth Kaushansky
- Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, California 92103-3931, USA.
| |
Collapse
|
|
11
|
Burmester H, Wolber EM, Freitag P, Fandrey J, Jelkmann W. Thrombopoietin production in wild-type and interleukin-6 knockout mice with acute inflammation. J Interferon Cytokine Res 2005; 25:407-13. [PMID: 16022585 DOI: 10.1089/jir.2005.25.407] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Clinical and laboratory studies indicate that thrombopoietin (TPO) gene expression increases during inflammation. To clarify the role of interleukin 6 (IL-6) in this process, blood cell counts, plasma TPO concentrations, and hepatic and renal TPO mRNA levels were investigated in wild-type and IL-6 knockout mice, with sterile abscesses produced by subcutaneous injection of turpentine oil. Treatment did not cause a change in blood cell counts during the 72 h period of observation. The numbers of thrombocytes and erythrocytes were slightly lower in the IL-6 knockout mice than in the wild-type littermates under all conditions. Plasma IL-6 and TPO concentrations increased on turpentine injection only in the wild-type mice. In addition, turpentine treatment of these caused an increase in hepatic TPO mRNA levels as assessed by competitive polymerase chain reaction (RT-PCR) and real-time PCR, whereas renal TPO mRNA levels were unaltered. TPO mRNA levels did not increase in the livers of IL-6 knockout mice on turpentine treatment. These results support the concept that TPO behaves like an acute-phase protein in that its synthesis is induced by IL-6 in the liver.
Collapse
Affiliation(s)
- Helen Burmester
- Institute of Physiology, University of Luebeck, Luebeck, Germany
| | | | | | | | | |
Collapse
|
|
12
|
Anatol P, Robert F, Danuta P. Effect of interferon alpha2b plus ribavirin treatment on selected growth factors in respect to inflammation and fibrosis in chronic hepatitis C. World J Gastroenterol 2005; 11:1854-8. [PMID: 15793880 PMCID: PMC4305890 DOI: 10.3748/wjg.v11.i12.1854] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Growth factors (GF) that participate in regeneration and apoptosis have an important role in chronic liver diseases. We analyzed serum GF concentration during antiviral treatment and correlated it with morphological liver failure in chronic hepatitis C.
METHODS: The levels of GF were determined in sera by ELISA method in 0, 16, 32 and 48 wk of therapy in 40 patients treated with IFNα2b (9 MU sc/wk) and RBV (1.2 g/d) and in 25 healthy subjects. Blind liver biopsies were done before treatment with histological grading and staging examination.
RESULTS: The hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were markedly elevated prior the treatment and decreased during the therapy, although they did not reach the normal level. In non-responding (NR) patients, HGF and EGF were higher than that in responders (R), however differences were not significant. Before the treatment thrombopoietin (TPO) level was significantly lower in R than in NR (P<0.03). Platelet-derived growth factor (PDGF) concentration was lower in chronic hepatitis C than in healthy subjects and decreased during the treatment. A significant positive correlation was observed between inflammatory activity in the liver tissue and the concentration of HGF (in R: r = 0.4, in NR: r = 0.5), TPO (R: r = 0.6), and a significant negative correlation between this activity and EGF (R: r = -0.6) and PDGF (R: r = -0.5). Serum HGF concentration was higher in more advanced fibrosis (R: r = 0.5, P<0.05; NR: r = 0.4, P<0.03).
CONCLUSION: The decrease in PDGF can be an effective prognostic marker of the treatment and HCV elimination. Decreasing HGF, EGF, and PDGF can influence the inhibition of inflammatory and fibrotic processes in the liver during the antiviral treatment.
Collapse
Affiliation(s)
- Panasiuk Anatol
- Department of Infectious Diseases, Medical University of Bialystok, 15-540 Bialystok, Zurawia str. 14, Poland.
| | | | | |
Collapse
|
|
13
|
Dame C, Wolber EM, Freitag P, Hofmann D, Bartmann P, Fandrey J. Thrombopoietin gene expression in the developing human central nervous system. BRAIN RESEARCH. DEVELOPMENTAL BRAIN RESEARCH 2003; 143:217-23. [PMID: 12855193 DOI: 10.1016/s0165-3806(03)00134-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Thrombopoietin gene expression in the human adult central nervous system (CNS) appears to be locally restricted. The aim of this study was to identify areas of thrombopoietin expression in the developing human CNS, and to compare the thrombopoietin mRNA content in the CNS to that in liver and kidneys as major sites of thrombopoietin production. Thrombopoietin protein concentrations in the cerebrospinal fluid (CSF) were measured by ELISA. In 14 fetuses and neonates with perinatal death, thrombopoietin mRNA expression was measured by competitive RT-PCR. Thrombopoietin mRNA was expressed in 29 of 32 specimens taken from the CNS. The following ranking of the intensity of expression in the CNS was possible: Spinal cord=cerebellum=cortex>>pituitary gland>>>brain stem=corpora amygdala=hippocampus. Whereas in the latter three tissues only trace amounts of thrombopoietin transcripts were detectable, thrombopoietin mRNA levels in the spinal cord were comparable to levels in liver and kidney. Thrombopoietin protein concentrations in CSF ranged between 41 and 75 pg/ml. In the developing human CNS, the thrombopoietin gene is abundantly expressed. Considering that thrombopoietin contains a neurotrophic sequence, it may well play a role in neuronal cell biology.
Collapse
Affiliation(s)
- Christof Dame
- Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
| | | | | | | | | | | |
Collapse
|
|
14
|
Song LL, Luo HS, Yu BP. Effects of hepatocyte growth factor on fibrosis and hepatic expression of MMP-1 andTIMP-1. Shijie Huaren Xiaohua Zazhi 2003; 11:209-213. [DOI: 10.11569/wcjd.v11.i2.209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of hepatocyte growth factor (HGF) on severity of liver fibrosis and hepatic expressions of MMP-1, TIMP-1 and to explore the mechanism of HGF in preventing liver fibrosis in rats.
METHODS: Eighty male Wistar rats were randomly divided into normal control group (Group A, 16 rats), liver fibrosis model group (Group B, 54 rats) and HGF therapy group (Group C, 10 rats). The liver fibrosis model was induced by administration CCl4 intraperitoneally. Rats in Group C had been administered HGF for six weeks and were sacrificed afterwards. Eight rats from each of group A and B were randomly sacrificed on week 6 simultaneously as that in group C. The remaining rats in-group B were randomly further subdivided into liver fibrosis model group (Group D, 12 rats) and HGF therapy group (Group E, 10 rats), HGF was administered to rats in group E on week. 7.All rats in group D and E were sacrificed on week 10.Liver function and levels of serum hyaluronic acid (HA), mucin (LN), collegen type IV (CIV), procollagen III (PCIII) were tested; the expression of MMP-1 and TIMP-1 were determined by immunohistochemical staining and analyzed by computer.
RESULTS: Compared with Group B, the serum levels of ALT, AST, HA, LN, CIV, PCIII in Group C were significantly reduced (P < 0.01), MMP-1 activity was slightly increased (0.25 ± 0.02, vs 0.22 ± 0.05, P < 0.05), TIMP-1 activity was markedly reduced (0.34 ± 0.05, vs 0.45 ± 005, P < 0.01). TIMP-1 activity in Group E (0.31 ± 0.07) was also markedly reduced in comparison with Group D (0.42 ± 0.06) (P < 0.01).
CONCLUSIONS: HGF has obvious effect in preventing development of liver fibrosis; it might facilitate degradation of hepatic fibrosic tissue via increasing the MMP-1 activity and or inhibiting TIMP-1 activity.
Collapse
|
|
15
|
Wolber EM, Haase B, Jelkmann W. Thrombopoietin production in human hepatic cell cultures (HepG2) is resistant to IFN-alpha, IFN-beta, and IFN-gamma treatment. J Interferon Cytokine Res 2002; 22:1185-9. [PMID: 12581491 DOI: 10.1089/10799900260475704] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Thrombocytopenia is an important complication of interferon (IFN) therapy for chronic viral hepatitis. To study whether IFN interferes with hepatic thrombopoietin (TPO) synthesis, we used the human hepatoma cell line HepG2. Our results show that IFN-alpha, IFN-beta, or IFN-gamma did not impair TPO mRNA expression, as determined by quantitative RT-PCR, even when high IFN doses (up to 5000 U/ml) or long-term incubations (up to 14 days) were applied. Neither was the rate of secretion of immunoreactive TPO reduced on IFN treatment. These findings support the concept that IFNs primarily mediate effects on megakaryocytic cells and platelets rather than on TPO-producing hepatocytes.
Collapse
Affiliation(s)
- Eva-Maria Wolber
- Division of Hematology and Oncology, Harvard Institutes of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | | | | |
Collapse
|
|
16
|
Abstract
Blood platelets are here presented as active players in antimicrobial host defense and the induction of inflammation and tissue repair in addition to their participation in hemostasis. Megakaryopoiesis is inhibited after acute infection with viruses or bacteria. In contrast, chronic inflammation is often associated with reactive thrombocytosis. Platelets can bind and internalize pathogens and release microbicidal proteins that kill certain bacteria and fungi. By making cell-cell contacts with leukocytes and endothelial cells, platelets assist white blood cells in rolling, arrest and transmigration. On stimulation by bacteria or thrombin, platelets release the content of their alpha-granules, which include an arsenal of bioactive peptides, such as CC-chemokines and CXC-chemokines and growth factors for endothelial cells, smooth muscle cells and fibroblasts. Thus, integral to innate immunity, the tiny little platelets may become bombshells when irritated by pathogens.
Collapse
|
|
17
|
Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis D virus genotypes in intravenous drug users in taiwan: decreasing prevalence and lack of correlation with hepatitis B virus genotypes. J Clin Microbiol 2002; 40:3047-9. [PMID: 12149376 PMCID: PMC120675 DOI: 10.1128/jcm.40.8.3047-3049.2002] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Of 368 hepatitis B virus (HBV)-infected intravenous drug users, 144 (39%) were positive for antibody to hepatitis D virus (anti-HDV). Anti-HDV-positive HBV carriers had a lower rate of positivity for HBV DNA than did anti-HDV-negative carriers (52 versus 73%, respectively). From 1986 to 1997, the average rate of decrease in the prevalence of HDV infection in this population was 4.7%/year.
Collapse
Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
| | | | | | | |
Collapse
|
|
18
|
Tacke F, Trautwein C, Zhao S, Andreeff M, Manns MP, Ganser A, Schöffski P. Quantification of hepatic thrombopoietin mRNA transcripts in patients with chronic liver diseases shows maintained gene expression in different etiologies of liver cirrhosis. LIVER 2002; 22:205-12. [PMID: 12100570 DOI: 10.1034/j.1600-0676.2002.01642.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired hepatic TPO production. As we reported previously, TPO serum levels are not decreased in patients with liver diseases compared with healthy controls and do not depend on the stage of cirrhosis or platelet count, but are highly elevated in patients with chronic virus hepatitis. METHODS To study possible mechanisms, we measured hepatic TPO mRNA levels in liver tissue samples from 31 liver cirrhosis patients by quantitative TaqMan real-time RT-PCR and corresponding serum TPO concentrations by ELISA. RESULTS Median TPO serum levels were elevated in patients with viral hepatitis (n = 12) compared with patients with a biliary (n = 10), alcoholic (n = 6) or other (n = 3) disease etiology, while hepatic TPO mRNA levels did not differ. The TPO mRNA levels in patients with chronic liver diseases were not different from normal liver tissue sample. The TPO mRNA and TPO serum level did not correlate. CONCLUSIONS We conclude that hepatic TPO gene expression appears to be maintained on a constitutive transcriptional level in patients with liver diseases and does not change dependent on disease etiology.
Collapse
Affiliation(s)
- Frank Tacke
- Department of Gastroenterology and Hepatology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
The liver plays an important role in the production of haemopoietic hormones. It acts as the primary site of synthesis of erythropoietin (EPO) in the fetal stage, and it is the predominant thrombopoietin (TPO)-producing organ for life. In contrast to that of EPO and other liver proteins, the hepatic synthesis of TPO is influenced little by external signals. Hepatocytes express the TPO gene in a constitutive way, i.e. irrespective of the level of platelets in blood. Megakaryocytes and platelets remove the hormone from blood by means of their high-affinity TPO receptors. Normally, the plasma level of TPO is relatively low ( approximately 10(-12) mol/l). However, in thrombocytopenic states due to marrow failure or bleeding, the concentration of circulating TPO may increase greatly. The simple feedback regulation by TPO and its target cells is efficient in maintaining constant platelet numbers in healthy people. Persisting thrombocytopenia develops only in severe liver or marrow failure. On the other hand, an increase in circulating TPO and interleukin 6 (IL-6) may cause reactive thrombocytosis in inflammatory diseases, including cancer. The indications for recombinant human thrombopoietin (rHuTPO) therapy and its impact on transfusion medicine are still under investigation.
Collapse
Affiliation(s)
- W Jelkmann
- Institute of Physiology, Medical University of Lubeck, Lubeck, Germany.
| |
Collapse
|