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Pharmaceutics
Special Issues
Antifibrotic Drugs
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Antifibrotic Drugs

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (15 December 2019) | Viewed by 22239

Special Issue Editor

Prof. Dr. Peter Olinga

E-Mail Website
Guest Editor
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Interests: organ fibrosis; antifibrotic drugs; animal models of fibrosis; antifibrotic targets; in vitro models of fibrosis; mechanism of fibrosis

Special Issue Information

Dear Colleagues,

Fibrosis is an exaggerated wound-healing response to chronic tissue damage. Fibrosis affects nearly all tissues and organ systems and ultimately results in organ failure. Diseases leading to fibrosis are an increasing clinical and economic burden. It is estimated that fibrosis contributes to almost 45% of deaths in the developed world, as this pathology is a feature of numerous conditions (e.g., persistent viral infections and autoimmune reactions) across multiple organs. Despite the progress made in the field of fibrosis research, the clinical success rate in antifibrotic drug development is very limited. Therefore, this Special Issue will discuss promising new targets to treat organ fibrosis and potential antifibrotic drugs. Furthermore, there will be an emphasis on targeted delivery and formulation of potential antifibrotic drugs. Animal models of fibrosis rarely predict the success of antifibrotic drugs in humans. Hence, this issue will deliberate novel models that better predict the efficacy of antifibrotic drug in humans.

Prof. Dr. Peter Olinga
Guest Editor

Manuscript Submission Information

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Keywords

  • organ fibrosis
  • antifibrotic drugs
  • animal models of fibrosis
  • antifibrotic targets
  • in vitro models of fibrosis
  • mechanism of fibrosis

Published Papers (6 papers)

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Research

21 pages, 13241 KiB  
Article
Osteoprotegerin Is more than a Possible Serum Marker in Liver Fibrosis: A Study into Its Function in Human and Murine Liver
by Adhyatmika Adhyatmika, Leonie Beljaars, Kurnia S. S. Putri, Habibie Habibie, Carian E. Boorsma, Catharina Reker-Smit, Theerut Luangmonkong, Burak Guney, Axel Haak, Keri A. Mangnus, Eduard Post, Klaas Poelstra, Kim Ravnskjaer, Peter Olinga and Barbro N. Melgert
Pharmaceutics 2020, 12(5), 471; https://doi.org/10.3390/pharmaceutics12050471 - 21 May 2020
Cited by 15 | Viewed by 3560
Abstract
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we [...] Read more.
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers. OPG levels were significantly higher in lysates of human and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with decreased production of OPG compared to ongoing fibrosis. OPG may stimulate fibrogenesis through TGFβ1 and is associated with the degree of fibrogenesis. It should therefore be investigated further as a possible drug target for liver fibrosis or biomarker for treatment success of novel antifibrotics. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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31 pages, 36839 KiB  
Article
Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis
by Emilia Bigaeva, Nataly Puerta Cavanzo, Elisabeth G. D. Stribos, Amos J. de Jong, Carin Biel, Henricus A. M. Mutsaers, Michael S. Jensen, Rikke Nørregaard, Anna M. Leliveld, Igle J. de Jong, Jan-Luuk Hillebrands, Harry van Goor, Miriam Boersema, Ruud A. Bank and Peter Olinga
Pharmaceutics 2020, 12(5), 459; https://doi.org/10.3390/pharmaceutics12050459 - 18 May 2020
Cited by 14 | Viewed by 4440
Abstract
Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of [...] Read more.
Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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11 pages, 1140 KiB  
Article
Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing
by Kaj E. C. Blokland, David W. Waters, Michael Schuliga, Jane Read, Simon D. Pouwels, Christopher L. Grainge, Jade Jaffar, Glen Westall, Steven E. Mutsaers, Cecilia M. Prêle, Janette K. Burgess and Darryl A. Knight
Pharmaceutics 2020, 12(4), 389; https://doi.org/10.3390/pharmaceutics12040389 - 24 Apr 2020
Cited by 27 | Viewed by 5651
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair response. Recent work has shown that IPF-LFs display increased characteristics of senescence including growth arrest and a senescence-associated secretory phenotype (SASP) suggesting that senescent LFs contribute to dysfunctional wound repair process. Here, we investigated the influence of senescent LFs on alveolar epithelial cell repair responses in a co-culture system. Alveolar epithelial cell proliferation was attenuated when in co-culture with cells or conditioned media from, senescence-induced control LFs or IPF-LFs. Cell-cycle analyses showed that a larger number of epithelial cells were arrested in G2/M phase when co-cultured with IPF-LFs, than in monoculture. Paradoxically, the presence of LFs resulted in increased A549 migration after mechanical injury. Our data suggest that senescent LFs may contribute to aberrant re-epithelialization by inhibiting proliferation in IPF. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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15 pages, 11036 KiB  
Article
Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration
by Mikkel Ø. Nørgård, Michael Christensen, Henricus A.M. Mutsaers and Rikke Nørregaard
Pharmaceutics 2020, 12(4), 301; https://doi.org/10.3390/pharmaceutics12040301 - 26 Mar 2020
Cited by 2 | Viewed by 2511
Abstract
Phenformin and metformin are antihyperglycemic drugs that belong to the class of biguanides. Previously, we demonstrated that metformin elicits renoprotective effects in unilateral ureteral obstructed mice by reducing the infiltration of immune cells into the kidney. Since phenformin is a more potent drug [...] Read more.
Phenformin and metformin are antihyperglycemic drugs that belong to the class of biguanides. Previously, we demonstrated that metformin elicits renoprotective effects in unilateral ureteral obstructed mice by reducing the infiltration of immune cells into the kidney. Since phenformin is a more potent drug as compared to metformin, we investigated the renoprotective properties of phenformin. We studied the efficacy of both drugs using mice that underwent unilateral ureteral obstruction. Renal damage was evaluated on RNA and protein level by qPCR, Western blotting, and immunohistochemistry. Moreover, we studied immune cell infiltration using flow cytometry. Both biguanides significantly reduced UUO-induced kidney injury, as illustrated by a reduction in KIM-1 protein expression. In addition, both metformin and phenformin impacted the gene expression of several inflammatory markers but to a different extent. Moreover, in contrast to metformin, phenformin did not impact immune cell infiltration into UUO kidneys. In conclusion, we demonstrated that phenformin has similar renoprotective effects as metformin, but the mechanism of action differs, and phenformin is more potent. The beneficial effects of phenformin are probably due to inhibition of the STAT3 pathway and mitochondrial complex I. Further research is needed to unveil the therapeutic potential of phenformin for the treatment of renal injury, either at low, non-toxic concentrations or as part of a combination therapy. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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15 pages, 2188 KiB  
Article
Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis
by Fransien van Dijk, Christa M. Hazelhoff, Eduard Post, Gerian G. H. Prins, Krista Rombouts, Klaas Poelstra, Peter Olinga and Leonie Beljaars
Pharmaceutics 2020, 12(3), 278; https://doi.org/10.3390/pharmaceutics12030278 - 20 Mar 2020
Cited by 5 | Viewed by 3296
Abstract
The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, [...] Read more.
The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human stellate cells, ranging from primary cells to cell lines with an HSC-origin, and human liver slices and stimulated them with two key profibrotic factors, i.e., transforming growth factor β (TGFβ) or platelet-derived growth factor BB (PDGF-BB). We demonstrated that freshly isolated HSCs showed the strongest and highest variety of responses to these profibrotic stimuli, in particular following PDGF-BB stimulation, while cell lines were limited in their responses. Moreover, we verified these gene expression profiles in human precision-cut liver slices and showed similarities with the TGFβ- and PDGF-BB-related fibrotic responses, as observed in the primary HSCs. With this study, we encourage researchers to get off the beaten track when testing antifibrotic compounds by including more HSC-related markers in their future work. This way, potential compounds will be screened more extensively, which might increase the likelihood of developing effective antifibrotic drugs. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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12 pages, 2157 KiB  
Article
Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots
by Nathan A. Rohner, Dung Nguyen and Horst A. von Recum
Pharmaceutics 2020, 12(3), 275; https://doi.org/10.3390/pharmaceutics12030275 - 17 Mar 2020
Cited by 4 | Viewed by 2268
Abstract
For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition [...] Read more.
For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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