Fibrogenesis is a physiological process of tissue repair triggered by acute inflammation, but in chronic inflammation it may become a progressive and independent process leading to fibrosis [...]

Latella G.

Viscido A.

IRIS Università degli Studi dell'Aquila

cellsCommentCould Pirfenidone Also be Effective in TreatingIntestinal Fibrosis?Giovanni Latella * and Angelo ViscidoGastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila,Piazza S. Tommasi n.1, Coppito, 67100 L’Aquila, Italy; angelo.viscido@univaq.it* Correspondence: giolatel@tin.it; Tel.: +39-0862-434735; Fax: +39-0862-433425Received: 19 June 2020; Accepted: 21 July 2020; Published: 23 July 2020Fibrogenesis is a physiological process of tissue repair triggered by acute inflammation, but inchronic inflammation it may become a progressive and independent process leading to fibrosis [1].Fibrosis is characterized by an excessive local accumulation of extracellular matrix (ECM) proteins(mainly collagen), due to an increase in their production by activated fibroblasts and myofibroblastsand/or the reduction in their degradation by specific matrix metalloproteinases (MMPs).Intestinal fibrosis is a common outcome in inflammatory bowel diseases (IBD), especially inCrohn’s disease (CD) in which it becomes clinically apparent in up to 40% of patients. In CD, fibrosis maylead to intestinal fibrostrictures and even obstruction, that requires surgery [2]. Intestinal fibrostricturesare currently treated by endoscopic pneumatic dilations and surgical procedures, but even after surgery,there is a high rate of recurrence often leading to further surgical procedures. The cellular and molecularmechanisms underlying the formation of intestinal fibrostrictures in CD are not understood. Currently,effective pharmacological treatments to control or reverse the fibrosis process are unavailable.Several putative antifibrotic compounds have been tested, but only pirfenidone has recently beenapproved for the treatment of pulmonary fibrosis [3]. Therefore, it has been suggested that pirfenidonecould also be effective in the treatment of intestinal fibrosis.In a recent issue of Cells, Cui Y et al. have evaluated the anti-proliferative and anti-fibrotic propertiesof pirfenidone on primary human intestinal fibroblasts (p-HIFs) [4]. Pirfenidone dose-dependentlyinhibited p-HIF proliferation and motility, without inducing cell death, a reversible inhibition.Furthermore, Pirfenidone reduced mRNA levels of gene encoding ECM proteins like COL1A1,COL3A1, COL4A1, COL6A1, FN1 (encoding fibronectin 1) and ELN (encoding elastin), while it didnot affect ACTA2 (encoding alpha-smooth muscle actin: α-SMA considered a marker of activatedmyofibroblasts). Pirfenidone also suppressed basal and TGF-β1-induced collagen I expression inp-HIFs. Pirfenidone inhibited the proliferation of intestinal fibroblasts and their production of thecollagen I by suppressing both basal and TGF-β1-induced phosphorylation of mTOR and p70S6K butwithout affecting the phosphorylation of SMAD2/3 and p38 MAPK.These results are of great interest but should be confirmed on human intestinal fibroblasts isolatedfrom both the intestines of healthy subjects and CD patients. In particular, they should be confirmedboth on fibroblasts from the mucosa of the colon and the terminal ileum, the latter being the segmentmost frequently affected by fibrostrictures in CD. The effects of Pirfenidone reported on fibroblastsfrom a normal colon could not be confirmed on fibroblasts from CD fibrostrictures.Kadir et al. reported that Pirfenidone inhibited the proliferation of fibroblasts from patients withactive CD and the production of MMP3 and increased αSMA expression but did not influence neitherthe tissue inhibitor of metalloproteinases-1 (TIMP-1), nor collagen production [5].Inhibition of intestinal fibroblast proliferation by pirfenidone has been reported in severalexperimental studies both in vitro and in vivo [6–11]. Pirfenidone has been shown to induce intestinalfibroblast apoptosis and to inhibit TGF-β1-induced HIF activities such as myofibroblast differentiationCells 2020, 9, 1762; doi:10.3390/cells9081762 www.mdpi.com/journal/cellsCells 2020, 9, 1762 2 of 3(α-SMA) and collagen production [7–10]. These effects of Pirfenidone were mediated by the inhibitionof several signalings, including Smad, PI3K/AKT, MAPK, and mTOR transduction pathways [7–10].Furthermore, pirfenidone can also act on heat shock protein 47 (Hsp47), plasminogen activatorinhibitor-1 (Pai-1), platelet-derived growth factors (PDGF), connective tissue growth factors (CTGF),and transient receptor potential ankyrin 1 (TRPA1) channel pathways [6,8,9]. The discrepanciesreported by the various studies on the effects of pirfenidone on these molecular pathways need tobe clarified.TGF-β1 represents the main driving force of fibrosis in numerous organs including the intestine.The pivotal pro-fibrogenic role of TGF-β1 can be achieved through the activation of different intracellularsignalings, including SMAD, MAPK and mTOR pathways [1]. However, it has not yet been establishedwhich of these TGF-β1 transduction pathways plays a major role in the modulation of inflammationand which in the modulation of fibrogenesis.The initiation, maintenance, and progression of intestinal fibrosis are probably linked to thepersistence of a possible pro-fibrogenic adaptive immune response by specific T helper (Th) lymphocytesthat trigger and maintain active the pro-fibrogenic functions of mesenchymal stromal cells (fibroblasts,myofibroblasts, pericytes, endothelial cells). Therefore, it would be very important to evaluate alsothe effect of Pirfenidone on the activation, polarization, and proliferation of the various Th subsets(Th1, Th2, Th9, Th17, Th22, Treg cells), some with pro-fibrogenic action others with anti-fibrogeniceffects [12]. Inhibition of pro-fibrogenic Th subsets could certainly reduce or even shut down thepro-fibrogenic activities of intestinal fibroblasts and myofibroblasts.The treatment with pirfenidone is often associated with gastrointestinal side effects,including dyspepsia, nausea, vomiting, abdominal pain and diarrhea. To avoid or at least minimizethese gastrointestinal side effects of Pirfenidone, which could be even more frequent and severe in CD,Cui et al. also suggest for pirfenidone the use of controlled intestinal release systems of the drugsimilar to as was done with mesalazine. Unfortunately, this hypothesis would be limited by the factthat pirfenidone demonstrated a poor topical efficacy [10].Some cases of colitis associated with the use of pirfenidone in pulmonary fibrosis were alsoreported [13]. Pirfenidone could have negative effects on intestinal epithelial cells (reducing theirproliferation, altering their junction proteins, inducing apoptosis) and therefore could alter thepermeability and the barrier function of the intestinal mucosa. The loss of the barrier function can leadto translocation in the mucosa of microbes, whose components or products continue to stimulate thelocal immune response responsible for chronic intestinal inflammation and related fibrosis. Therefore,in addition to the effects on the pro-fibrogenic functions of fibroblasts, it is also crucial to evaluate theeffects of pirfenidone on intestinal epithelial cells.Furthermore, it would be useful to evaluate whether the observed anti-fibrotic effects of pirfenidoneare entirely direct effects or partly secondary to its anti-inflammatory and anti-oxidant actions.In conclusion, pirfenidone has important therapeutic potential to be used as an anti-inflammatoryand anti-fibrotic agent also in IBD, especially in CD. However, further studies are needed to evaluateits effects not only on mesenchymal stromal cells, such as fibroblasts and myofibroblasts but also onimmune and epithelial cells, both in vitro experimental models and experimental models of chroniccolitis complicated by intestinal fibrosis [6,8,10,11].Funding: This research received no external funding.Acknowledgments: We thank our colleague Simona Pompili who with her comments have helped to improvethis manuscript.Conflicts of Interest: The authors have no conflicts of interest to declare and did not use any outside assistance inpreparing the manuscript.Cells 2020, 9, 1762 3 of 3References1. Latella, G.; Di Gregorio, J.; Flati, V.; Rieder, F.; Lawrance, I.C. Mechanisms of initiation and progression ofintestinal fibrosis in IBD. Scand J. Gastroenterol. 2015, 50, 53–65. [CrossRef] [PubMed]2. Rieder, F.; Latella, G.; Magro, F.; Yuksel, E.S.; Higgins, P.D.; Di Sabatino, A.; de Bruyn, J.R.; Rimola, J.;Brito, J.; Bettenworth, D.; et al. European Crohn’s and Colitis Organisation Topical Review on Prediction,Diagnosis and Management of Fibrostenosing Crohn’s Disease. J. Crohns Colitis 2016, 10, 873–885. [CrossRef][PubMed]3. Nathan, S.D.; Costabel, U.; Glaspole, I.; Glassberg, M.K.; Lancaster, L.H.; Lederer, D.J.; Pereira, C.A.;Trzaskoma, B.; Morgenthien, E.A.; Limb, S.L.; et al. Efficacy of Pirfenidone in the Context of Multiple DiseaseProgression Events in Patients With Idiopathic Pulmonary Fibrosis. Chest 2019, 155, 712–719. [CrossRef][PubMed]4. Cui, Y.; Zhang, M.; Leng, C.; Blokzijl, T.; Jansen, B.H.; Dijkstra, G.; Faber, K.N. Pirfenidone Inhibits CellProliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells 2020, 9, 775. [CrossRef][PubMed]5. Kadir, S.I.; Wenzel Kragstrup, T.; Dige, A.; Kok Jensen, S.; Dahlerup, J.F.; Kelsen, J. Pirfenidone inhibitsthe proliferation of fibroblasts from patients with active Crohn’s disease. Scand. J. Gastroenterol. 2016, 51,1321–1325. [CrossRef] [PubMed]6. Iswandana, R.; Pham, B.T.; Suriguga, S.; Luangmonkong, T.; van Wijk, L.A.; Jansen, Y.J.M.; Oosterhuis, D.;Mutsaers, H.A.M.; Olinga, P. Murine Precision-cut Intestinal Slices as a Potential Screening Tool for AntifibroticDrugs. Inflamm. Bowel Dis. 2020, 26, 678–686. [CrossRef] [PubMed]7. Sun, Y.; Zhang, Y.; Chi, P. Pirfenidone suppresses TGF-β1-induced human intestinal fibroblasts activitiesby regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway.Mol. Med. Rep. 2018, 18, 3907–3913. [CrossRef] [PubMed]8. Kurahara, L.H.; Hiraishi, K.; Hu, Y.; Koga, K.; Onitsuka, M.; Doi, M.; Aoyagi, K.; Takedatsu, H.; Kojima, D.;Fujihara, Y. Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis inExperimental Crohn’s Disease. Cell. Mol. Gastroenterol. Hepatol. 2017, 5, 299–318. [CrossRef] [PubMed]9. Sun, Y.W.; Zhang, Y.Y.; Ke, X.J.; Wu, X.J.; Chen, Z.F.; Chi, P. Pirfenidone prevents radiation-inducedintestinal fibrosis in rats by inhibiting fibroblast proliferation and differentiation and suppressing theTGF-β1/Smad/CTGF signaling pathway. Eur. J. Pharmacol. 2018, 822, 199–206. [CrossRef] [PubMed]10. Li, G.; Ren, J.; Hu, Q.; Deng, Y.; Chen, G.; Guo, K.; Li, R.; Li, Y.; Wu, L.; Wang, G.; et al. Oral pirfenidoneprotects against fibrosis by inhibiting fibroblast proliferation and TGF-β signaling in a murine colitis model.Biochem. Pharmacol. 2016, 117, 57–67. [CrossRef] [PubMed]11. Meier, R.; Lutz, C.; Cosín-Roger, J.; Fagagnini, S.; Bollmann, G.; Hünerwadel, A.; Mamie, C.; Lang, S.;Tchouboukov, A.; Weber, F.E.; et al. Decreased Fibrogenesis After Treatment with Pirfenidone in a NewlyDeveloped Mouse Model of Intestinal Fibrosis. Inflamm. Bowel. Dis. 2016, 22, 569–582. [CrossRef] [PubMed]12. Latella, G.; Viscido, A. Controversial Contribution of Th17/IL-17 toward the Immune Response in IntestinalFibrosis. Dig. Dis. Sci. 2020, 65, 1299–1306. [CrossRef] [PubMed]13. Fiddler, C.A.; Simler, N.; Parfrey, H.; Miremadi, A.; Chilvers, E.R. Severe Colitis Associated with PirfenidoneUse in Idiopathic Pulmonary Fibrosis. Ann. Am. Thorac. Soc. 2016, 13, 1430–1432. [CrossRef] [PubMed]© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Could Pirfenidone Also be Effective in Treating Intestinal Fibrosis?

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Could Pirfenidone Also be Effective in Treating Intestinal Fibrosis?

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