Limits...
Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus

The neutrotrophin receptor as a therapeutic target.(A) The tyrosine kinase NGFR p75 is significantly upregulated in HSCs during cancerogenesis. In this experiment, the expression of NGFR p75 was analyzed by Western blot in human specimens derived from non-tumor and tumor areas of HCC patients. The analysis revealed a strong upregulation of NGFRp75 in diseased liver areas. The following antibodies were used in this set of experiments: NGFR p75 (sc-6188, Santa Cruz Biotech, Santa Cruz, CA, USA), α-SMA (CBL171, Cymbus Biotech, Hampshire, UK), glial fibrilliary acidic protein (GFAP, sc-6170, Santa Cruz), β-actin (A5441, Sigma, Taufkirchen, Germany). The membrane was counterstained with Ponceau S to document equal gel loading. The striking difference in protein content in sample “patient 8” was due to extremely high bilirubin content in this probe. (B) Immunhistochemical analysis of NGFR p75 and α-SMA expression in human samples obtained from normal and tumorigenic liver samples. Please note the strong expression of NGFR p75 in cells that were stained positive for α-SMA that becomes visible in the merged images. Cells were counterstained with DAPI. Magnifications were 100x (upper two panels) or 200x (lower two panels). The usage of human samples is covered by an ethical vote from the relevant authority (Institutional Review Board of the Bonn University Ethics Committee, decision #067/10). The results depicted in this figure are similar to a variety of previous studies that have already shown that NGFR p75 is expressed by HSC and strongly upregulated during transdifferentiation (Trim et al., 2000; Cassiman et al., 2001; Asai et al., 2006; Passino et al., 2007; Kendall et al., 2009; Zvibel et al., 2010; Reetz et al., 2013; Patil et al., 2014).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4764688&req=5

Figure 2: The neutrotrophin receptor as a therapeutic target.(A) The tyrosine kinase NGFR p75 is significantly upregulated in HSCs during cancerogenesis. In this experiment, the expression of NGFR p75 was analyzed by Western blot in human specimens derived from non-tumor and tumor areas of HCC patients. The analysis revealed a strong upregulation of NGFRp75 in diseased liver areas. The following antibodies were used in this set of experiments: NGFR p75 (sc-6188, Santa Cruz Biotech, Santa Cruz, CA, USA), α-SMA (CBL171, Cymbus Biotech, Hampshire, UK), glial fibrilliary acidic protein (GFAP, sc-6170, Santa Cruz), β-actin (A5441, Sigma, Taufkirchen, Germany). The membrane was counterstained with Ponceau S to document equal gel loading. The striking difference in protein content in sample “patient 8” was due to extremely high bilirubin content in this probe. (B) Immunhistochemical analysis of NGFR p75 and α-SMA expression in human samples obtained from normal and tumorigenic liver samples. Please note the strong expression of NGFR p75 in cells that were stained positive for α-SMA that becomes visible in the merged images. Cells were counterstained with DAPI. Magnifications were 100x (upper two panels) or 200x (lower two panels). The usage of human samples is covered by an ethical vote from the relevant authority (Institutional Review Board of the Bonn University Ethics Committee, decision #067/10). The results depicted in this figure are similar to a variety of previous studies that have already shown that NGFR p75 is expressed by HSC and strongly upregulated during transdifferentiation (Trim et al., 2000; Cassiman et al., 2001; Asai et al., 2006; Passino et al., 2007; Kendall et al., 2009; Zvibel et al., 2010; Reetz et al., 2013; Patil et al., 2014).

Mentions: The first step on the path to targeted delivery was made by Beljaars et al. (1999), when they developed and tested a carrier, designed to specifically bind to the M6P/IGF-II receptor on activated HSCs. This receptor is strongly activated during transdifferention of HSC and is closely associated with expression of α-SMA and the pathophysiology of liver disease (Trim et al., 2000; Cassiman et al., 2001). For example, it is strongly upregulated in HSC during hepatic carcinogenesis (Figure 2).


Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

The neutrotrophin receptor as a therapeutic target.(A) The tyrosine kinase NGFR p75 is significantly upregulated in HSCs during cancerogenesis. In this experiment, the expression of NGFR p75 was analyzed by Western blot in human specimens derived from non-tumor and tumor areas of HCC patients. The analysis revealed a strong upregulation of NGFRp75 in diseased liver areas. The following antibodies were used in this set of experiments: NGFR p75 (sc-6188, Santa Cruz Biotech, Santa Cruz, CA, USA), α-SMA (CBL171, Cymbus Biotech, Hampshire, UK), glial fibrilliary acidic protein (GFAP, sc-6170, Santa Cruz), β-actin (A5441, Sigma, Taufkirchen, Germany). The membrane was counterstained with Ponceau S to document equal gel loading. The striking difference in protein content in sample “patient 8” was due to extremely high bilirubin content in this probe. (B) Immunhistochemical analysis of NGFR p75 and α-SMA expression in human samples obtained from normal and tumorigenic liver samples. Please note the strong expression of NGFR p75 in cells that were stained positive for α-SMA that becomes visible in the merged images. Cells were counterstained with DAPI. Magnifications were 100x (upper two panels) or 200x (lower two panels). The usage of human samples is covered by an ethical vote from the relevant authority (Institutional Review Board of the Bonn University Ethics Committee, decision #067/10). The results depicted in this figure are similar to a variety of previous studies that have already shown that NGFR p75 is expressed by HSC and strongly upregulated during transdifferentiation (Trim et al., 2000; Cassiman et al., 2001; Asai et al., 2006; Passino et al., 2007; Kendall et al., 2009; Zvibel et al., 2010; Reetz et al., 2013; Patil et al., 2014).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764688&req=5

Figure 2: The neutrotrophin receptor as a therapeutic target.(A) The tyrosine kinase NGFR p75 is significantly upregulated in HSCs during cancerogenesis. In this experiment, the expression of NGFR p75 was analyzed by Western blot in human specimens derived from non-tumor and tumor areas of HCC patients. The analysis revealed a strong upregulation of NGFRp75 in diseased liver areas. The following antibodies were used in this set of experiments: NGFR p75 (sc-6188, Santa Cruz Biotech, Santa Cruz, CA, USA), α-SMA (CBL171, Cymbus Biotech, Hampshire, UK), glial fibrilliary acidic protein (GFAP, sc-6170, Santa Cruz), β-actin (A5441, Sigma, Taufkirchen, Germany). The membrane was counterstained with Ponceau S to document equal gel loading. The striking difference in protein content in sample “patient 8” was due to extremely high bilirubin content in this probe. (B) Immunhistochemical analysis of NGFR p75 and α-SMA expression in human samples obtained from normal and tumorigenic liver samples. Please note the strong expression of NGFR p75 in cells that were stained positive for α-SMA that becomes visible in the merged images. Cells were counterstained with DAPI. Magnifications were 100x (upper two panels) or 200x (lower two panels). The usage of human samples is covered by an ethical vote from the relevant authority (Institutional Review Board of the Bonn University Ethics Committee, decision #067/10). The results depicted in this figure are similar to a variety of previous studies that have already shown that NGFR p75 is expressed by HSC and strongly upregulated during transdifferentiation (Trim et al., 2000; Cassiman et al., 2001; Asai et al., 2006; Passino et al., 2007; Kendall et al., 2009; Zvibel et al., 2010; Reetz et al., 2013; Patil et al., 2014).
Mentions: The first step on the path to targeted delivery was made by Beljaars et al. (1999), when they developed and tested a carrier, designed to specifically bind to the M6P/IGF-II receptor on activated HSCs. This receptor is strongly activated during transdifferention of HSC and is closely associated with expression of α-SMA and the pathophysiology of liver disease (Trim et al., 2000; Cassiman et al., 2001). For example, it is strongly upregulated in HSC during hepatic carcinogenesis (Figure 2).

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus