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. 2004 Mar;53(3):438-45.
doi: 10.1136/gut.2003.026658.

Hepatic fibrogenesis requires sympathetic neurotransmitters

J A Oben  1 , T Roskams, S Yang, H Lin, N Sinelli, M Torbenson, U Smedh, T H Moran, Z Li, J Huang, S A Thomas, A M Diehl
Affiliations

VSports注册入口 - Hepatic fibrogenesis requires sympathetic neurotransmitters

J A Oben et al. Gut. 2004 Mar.

Abstract

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear VSports手机版. .

Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis V体育安卓版. .

Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists V体育ios版. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. .

Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis. VSports最新版本.

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"VSports app下载" Figures

Figure 1
Figure 1
Expression of tyrosine hydroxylase and dopamine β-hydroxylase by cultured hepatic stellate cells (HSC). HSC from six healthy adult mice were pooled and cultured for four days. Lysates were evaluated by immunoblot (10 μg protein/lane).
Figure 2
Figure 2
Primary hepatic stellate cell (HSC) synthesise and release of norepinephrine (NE) in culture. HSC pooled from six normal mice were cultured for four days. Cell lysates and conditioned media were analysed by high pressure liquid chromatography. DOPAC, 3,4-dihydroxyphenylacetic acid; DBA, dihydroxybenzilamine; DA, dopamine; 5-HIAA, 5-hydroxyindoleacetic acid; HVA, homovallinic acid; 5-HT, 5-hydroxytryptamine.
Figure 3
Figure 3
Hepatic stellate cells (HSC) express multiple adrenoceptor subtypes. RNA obtained by pooling HSC from six normal mice was analysed by reverse transcription-polymerase chain reaction. First lane, DNA ladder (500–200 bp, arrowed). Each subsequent pair of lanes is a replicate analysis of adrenoceptor genes. The 18S band (324 bp) serves as a control.
Figure 4
Figure 4
Adrenoceptor antagonists inhibited the growth of primary hepatic stellate cell (HSC) cultures. Freshly isolated HSC pooled from six normal mice were cultured with prazosin (PRZ 10 μM) and propranolol (PRL 10 μM) alone and PRZ+PRL (PP). After 48 hours, cell numbers were evaluated. Data (mean (SD)) are from two separate experiments. *p<0.05 for PRZ or PRL treated HSC versus control, ††p<0.01 for PP treated HSC versus control.
Figure 5
Figure 5
Hepatic stellate cells (HSC) that are genetically incapable of producing norepinephrine (NE) grow poorly in culture and exogenous NE rescues proliferative activity. Representative photomicrographs of pooled HSC isolated from six Dbh+/− mice cultured without (A) or with (B) prazosin (PRZ 10 μM) for four days, and four day old cultures of HSC pooled from six control Dbh−/− mice (C). HSC from six additional Dbh−/− mice were cultured in control medium or medium+NE (10 μM) for four days and HSC numbers were quantified (D). *p<0.05 versus control.
Figure 6
Figure 6
Norepinephrine (NE) activates adrenoceptor G protein coupled mechanisms that induce mitogenic and survival pathways in hepatic stellate cells (HSC). HSC pooled from six normal mice were cultured with NE (10 μM) or NE with pertussis toxin (NE+PT), wortmannin (NE+WT), PD98059 (NE+PD), SB202190 (NE+SB), or Ro-32-0432 (NE+RO). After two days, HSC numbers were evaluated in triplicate wells. Mean (SEM) results of duplicate experiments are shown. *p<0.05 for inhibitor treated versus NE alone.
Figure 7
Figure 7
Norepinephrine (NE) increases hepatic stellate cell (HSC) activation in NE deficient ob/ob mice. Ob/ob mice were treated with NE (n = 5) or vehicle (n = 10). After four weeks, glial acidic fibrillary protein positive cells were counted in five randomly selected high power fields/liver section from each animal. Data are mean (SD). *p<0.05 for ob/ob control versus lean control; †p<0.05 for ob/ob+NE versus ob/ob control.
Figure 8
Figure 8
Figure 9
Figure 9
Reduced activation of hepatic stellate cells (HSC) in norepinephrine (NE) deficient Dbh−/− mice. Twelve Dbh−/− and six of their control Dbh+/− littermates were fed methionine choline deficient (MCD) diets. Half of the Dbh−/− mice were also infused with isoprenaline (ISO) for four weeks. (A) Alpha smooth muscle actin (ASMA)+ve sinusoidal cells were counted in five randomly selected fields/liver section from each mouse. Mean (SD) results of one experiment are shown. *p<0.05 for Dbh+/− versus Dbh−/− control; †p<0.05 for Dbh−/− control versus Dbh−/− +ISO. Identical results have since been obtained in a second experiment that studied an additional 12 mice (four mice/group). (B) Photomicrograph from representative Dbh+/− mice. (C) Photomicrograph from typical Dbh−/− mice. Arrows indicate typical ASMA+ve HSC (B) or vessel wall (C).
Figure 10
Figure 10
Norepinephrine (NE) regulates hepatic expression of collagen and transforming growth factor β1 (TGF-β). Liver RNA was isolated from six Dbh+/− mice, six Dbh−/− mice, and six Dbh−/− mice that were infused with isoprenaline (ISO). All mice had been fed methionine choline deficient (MCD) diets for four weeks. Hepatic expression of collagen-1-α1 (Col1-α1) (A) and TGF-β (B) was evaluated by ribonuclease protection assay (20 μg RNA/assay). A representative phosphoimage displays individual data from three mice/group from the first ribonuclease protection assay. Normalised mean (SD) collagen (n = 12; six mice/group) and TGF-β1 gene expression from all 18 mice (six mice/group) are shown. *p<0.05 for Dbh+/− versus Dbh−/− mice; †p<0.05 for Dbh−/− versus Dbh−/−+ISO.
Figure 11
Figure 11
Figure 12
Figure 12
Figure 13
Figure 13
Norepinephrine (NE) increases hepatic expression of collagen and transforming growth factor β1 (TGF-β) without increasing liver injury in NE deficient ob/ob mice. Liver RNA was isolated from five control ob/ob mice and five NE treated ob/ob mice. In each mouse, hepatic expression of collagen-1-α1 (Col1-α1) (A) and TGF-β (B) was evaluated by ribonuclease protection assay (20 μgRNA/assay). A representative phosphoimage demonstrating individual data from two animals per group is shown. Normalised mean (SD) collagen and TGF-β1 gene expression in all mice are shown. *p<0.05 control ob/ob versus ob/ob+NE. (C) Mason-trichrome stained sections from a representative control ob/ob mouse and from an NE treated ob/ob mouse with pericellular and sinusoidal fibrosis. (D) Mean (SEM) alanine aminotransferase (ALT) values in the control and NE treated groups of ob/ob mice. *p<0.05 for NE treated ob/ob versus ob/ob controls.
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References

    1. Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000;275:2247–50. - PubMed
    1. Reynaert H, Thompson MG, Thomas T, et al. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut 2002;50:571–81. - PMC - PubMed
    1. Dubuisson L, Desmouliere A, Decourt B, et al. Inhibition of rat liver fibrogenesis through noradrenergic antagonism. Hepatology 2002;35:325–31. - PubMed
    1. Hsu CT. The role of the sympathetic nervous system in promoting liver cirrhosis induced by carbon tetrachloride, using the essential hypertensive animal (SHR). J Auton Nerv Syst 1992;37:163–73. - "VSports注册入口" PubMed
    1. Hsu CT. The role of the autonomic nervous system in chemically-induced liver damage and repair-using the essential hypertensive animal model (SHR). J Auton Nerv Syst 1995;51:135–42. - PubMed

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