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Antifibrotic activities of pirfenidone in animal models

C.J. Schaefer, D.W. Ruhrmund, L. Pan, S.D. Seiwert, K. Kossen
European Respiratory Review 2011 20: 85-97; DOI: 10.1183/09059180.00001111
C.J. Schaefer
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D.W. Ruhrmund
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L. Pan
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S.D. Seiwert
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K. Kossen
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  • For correspondence: kkossen@intermune.com
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  • Figure 1.
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    Figure 1.

    Chemical structure of pirfenidone.

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    Figure 2.

    The antifibrotic activity of pirfenidone in preclinical models of pulmonary fibrosis. a) Experimental design and effects of prophylactic pirfenidone treatment on bleomycin-induced pulmonary fibrosis [38]. b) Effects of delayed pirfenidone treatment on bleomycin-induced pulmonary fibrosis (H. Oku, Shionogi and Co. Ltd, Osaka, Japan; personal communication). c) Effects of prophylactic pirfenidone treatment on bleomycin-induced pulmonary fibrosis [44]. d) Experimental design and effects of pirfenidone in an orthotopic lung transplant model [45]. e) The effects of pirfenidone in a mouse model of airway remodelling and hyperresponsiveness induced by sensitisation and challenge with ovalbumin [47]. BAL: bronchoalveolar lavage; bFGF: basic fibroblast growth factor; IL: interleukin; IFN: interferon; OVA: ovalbumin; PDGF: platelet-derived growth factor; SD: Sprague-Dawley; SDF: stromal cell-derived factor; TGF: transforming growth factor.

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    Figure 3.

    Summary of activities observed in animal models and cell-based assays. ECM: extracellular matrix.

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  • Table 1. Effects of pirfenidone in animal models of lung, heart, kidney, and liver fibrosis
    SystemReferenceIn vivo modelSpeciesProtocolTotal daily dose/routeFibrosisFibrotic markersInflammatory markersOxidative stressFunctional end-points
    LungOku et al. [38]BleomycinMouseProphylactic10, 30*, 100* mg·kg−1 p.o.#DecreasedDecreasedDecreasedNANA
    H. Oku; personal communicationBleomycinMouseTherapeutic10, 30*, 100* mg·kg−1 p.o.#DecreasedNANANANA
    Kakugawa et al. [39]BleomycinMouseTherapeutic400* mg·kg−1 p.o.¶DecreasedDecreasedNANANA
    Iyer et al. [40]BleomycinHamsterProphylactic0.5%* in chowDecreasedDecreasedNADecreasedNA
    Iyer et al. [41]BleomycinHamsterTherapeutic+0.5%* in chowDecreasedDecreasedNADecreasedNA
    Iyer et al. [42]BleomycinHamsterProphylactic0.5%* in chowDecreasedDecreasedNADecreasedNA
    Gurujeyalakshmi et al. [43]BleomycinHamsterProphylactic0.5%* in chowNADecreasedNANANA
    Schelegle et al. [44]BleomycinHamsterProphylactic0.5%* in chowDecreasedNANANAImproved
    Liu et al. [45]TransplantRatProphylactic0.5%* in chowDecreasedDecreasedNANo effectImproved
    Zhou et al. [46]1) TransplantRatProphylactic0.5%* in chowDecreasedDecreasedNANANA
    2) TransplantRatTherapeutic0.5% in chowNo effectNANANANA
    Hirano et al. [47]Allergen induced dysfunctionMouseProphylactic125, 250, 500* mg·kg−1 s.c.§DecreasedDecreasedDecreasedNAImproved
    HeartLee et al. [2]Congestive heart failureDogProphylactic2400* mg p.o.#DecreasedDecreasedDecreasedNAImproved
    Nguyen et al. [3]MIRatTherapeutic1.2%* in chowDecreasedNANANAImproved
    Mirkovic et al. [33]HypertensionRatTherapeutic0.4%* in chowDecreasedNANANAImproved
    KidneyShimizu et al. [48]1) Continuous ureteral obstructionRatProphylactic0.6–0.9%* in chowDecreasedDecreasedNANANA
    2) Continuous ureteral obstructionRatTherapeutic0.6–0.9%ƒ in chowTrendDecreasedNANANA
    3) Temporary ureteral obstructionRatTherapeutic0.6–0.9%* in chowDecreasedNANANAImproved
    Takakura et al. [49]5/6 nephrectomyRatTherapeutic1%* in chowDecreasedDecreasedNANATrend
    Shimizu et al. [50]5/6 nephrectomyRatTherapeutic0.6–0.9%* in chowDecreasedDecreasedNANAImproved
    RamachandraRao et al. [51]Diabetic db/dbMouseTherapeutic0.5%* in chowDecreasedDecreasedNANANo effect
    LiverSalazar-Montes et al. [52]1) Carbon tetrachlorideRatTherapeutic200ƒ mg·kg−1 p.o.§TrendDecreasedNADecreasedImproved
    2) Bile duct ligationRatTherapeutic200* mg·kg−1 p.o.§DecreasedDecreasedNADecreasedNo effect
    Garcia et al. [53]1) Carbon tetrachlorideRatTherapeutic##500* mg·kg−1 p.o.DecreasedDecreasedNANAImproved
    2) Carbon tetrachlorideRatTherapeutic¶¶200* mg·kg−1 p.o.§DecreasedNANANANA
    3) Bile duct ligationRatProphylactic200*, 500 mg·kg−1 p.o.§DecreasedNANANANA
    Di Sario et al. [54]DimethylnitrosamineRatTherapeutic0.5%* in chowDecreasedDecreasedDecreasedNAImproved
    Tada et al. [55]DimethylnitrosamineRatProphylactic500* mg·kg−1 p.o.§DecreasedTrendNANANo effect
    • NA: not assessed; MI: myocardial infarction. *: statistically significant treatment effect (per reference); #: given in three divided daily doses; ¶: given in two divided daily doses; +: pirfenidone treatment initiated following the second of three bleomycin insults; §: given in one daily dose; ƒ: treatment-associated trend; ##: pirfenidone dosed following cessation of carbon tetrachloride; ¶¶: pirfenidone dosed in final 3 weeks of an 11-week model with continuous carbon tetrachloride.

  • Table 2. Cytokines and growth factors modulated by pirfenidone treatment in animal models
    Cytokine/growth factorLungHeartKidneyLiver
    Oku et al. [38]Hirano et al. [47]Liu et al. [45]Zhou et al. [46]Lee et al. [2]Shimizu et al. [50]Shimizu et al. [48]Salazar-Montes et al. [52]Garcia et al. [53]Di Sario et al. [54]Tada et al. [55]
    BleomycinAllergen-induced AHRTransplantTransplantChronic heart failure5/6 nephrectomyUreteral obstructionCCl4 and bile duct ligation modelsCCl4 and bile duct ligation modelsDMNDMN
    TGF-βProtein↓Protein↓Protein↓Protein↓Protein↓mRNA↓mRNA↓mRNA↓mRNA↓mRNA↓mRNA↓#
    PDGFProtein↓
    bFGFProtein↓
    IL-18Protein↓
    SDF-1α/CXCL12Protein↓
    IFN-γProtein↔
    HGFmRNA↑
    MMP-2mRNA↓Protein↔mRNA↓
    MMP-9Protein↓
    TIMP-1mRNA↓mRNA↓
    TIMP-4Protein↑
    TNF-αProtein↓Protein↓
    IL-1βProtein↓
    IL-4Protein↓
    IL-5Protein↓
    IL-13Protein↓
    IL-6Protein↓
    MCP-1Protein↓
    IL-12p40Protein↓
    • Empty fields denote end-points that were either not assessed or not dysregulated in this model. Unless otherwise noted, all effects were statistically significant per publication. AHR: airway hyperresponsiveness; DMN: dimethylnitrosamine; TGF: transforming growth factor; PDGF: platelet-derived growth factor; bFGF: basic fibroblast growth factor; IL: interleukin; SDF: stromal cell-derived factor; CXCL12: chemokine, CXC motif, ligand 12; IFN: interferon; HGF: hepatocyte growth factor; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase; TNF: tumour necrosis factor; MCP: monocyte chemoattractant protein. #: statistical significance not assessed.

  • Table 3. Antifibrotic effects in cell-based assays
    ReferenceSystemFibroblast proliferationECM productionFibrotic markers
    Di Sario et al. [79]Primary rat hepatic stellate cellsInhibited PDGF-stimulated proliferationReduced TGF-β induced collagen I (protein and mRNA)
    Ozes and Blatt [80]Human lung fibroblasts (HFL-1)Reduced TGF-β induced collagen (protein)
    Sulfab et al. [81]Human unbilical vein endothelial cells (HUVEC)Reduced TGF-β stimulated fibronectin, collagen IV, and thrombospondin-2 proteins#Reduced TGF-β stimulated ET-1, IGFBP-3 and TGF-β isoforms 1-3
    Nakayama et al. [82]Normal human lung fibroblasts (NHLF)Reduced TGF-β induced collagen I expression (protein and mRNA)Reduced TGF-β induced expression of the collagen chaperone HSP47 (protein and mRNA)
    Zhang et al. [83]Human retinal pigment epithelial (RPE) cellsReduced TGF-β induced fibronectin (protein) production
    Hewitson et al. [84]Rat renal fibroblast isolated after ureteral obstruction (a mixture of fibroblasts and myofibroblasts)Reduced fibroblast proliferationCollagen protein production unaffected (slight reduction)Reduced α-SMA and CTGF protein expression
    Lin et al. [85]Human tenon’s fibroblasts (isolated from eye and expanded)Reduced serum-stimulated fibroblast proliferation. Increased population of G1-phase cells and decreased S-phase.Reduced TGF-β1, -β2, and -β3 mRNA and protein expression; reduced fibroblast migration and collagen matrix contraction
    Lee et al. [86]Human myometrial and leiomyoma smooth muscle cells (benign uterine fibroid tumour cells)Reduced serum-stimulated fibroblast proliferationReduced collagen I and III mRNA expression
    • Blank boxes denote end-points that were not assessed. All results statistically significant (per reference) with the exception of one treatment related trend (#). ECM: extracellular matrix; PDGF: platelet derived growth factor; TGF: transforming growth factor; ET: endothelin; IGFBP: insulin-like growth factor binding protein; HSP: heat shock protein; SMA: smooth muscle actin; CTGF: connective tissue growth factor; G1-phase: gap 1 phase; S-phase: synthesis phase.

  • Table 4. Anti-inflammatory effects in cell-based assays
    ReferenceSystemInflammatory markers
    Grattendick et al. [87]Human mononuclear cell line (THP-1)Reduced LPS-induced secreted TNF-α
    Reduced LPS-induced cell-associated TNF-α
    Phillips et al. [88]Human peripheral blood mononuclear cells (PBMC)Decreased LPS-induced TNF-α, IL-1β, IFN-γ and GM-CSF; increased LPS-stimulated IL-10
    Reduced constitutive expression of IL-8, IL-6, and MIP-1β
    Nakazato et al. [89]Mouse macrophage cell line (RAW264.7)Reduced LPS-induced secreted TNF-α
    Reduced LPS-induced cell-associated TNF-α
    • LPS: lipopolysaccharide; TNF: tumour necrosis factor; IL: interleukin; IFN: interferon; GM-CSF: granulocyte-macrophage colony-stimulating factor; MIP: macrophage inflammatory protein.

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Antifibrotic activities of pirfenidone in animal models
C.J. Schaefer, D.W. Ruhrmund, L. Pan, S.D. Seiwert, K. Kossen
European Respiratory Review Jun 2011, 20 (120) 85-97; DOI: 10.1183/09059180.00001111

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Antifibrotic activities of pirfenidone in animal models
C.J. Schaefer, D.W. Ruhrmund, L. Pan, S.D. Seiwert, K. Kossen
European Respiratory Review Jun 2011, 20 (120) 85-97; DOI: 10.1183/09059180.00001111
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  • Article
    • Abstract
    • SUMMARY OF CLINICAL TRIALS IN IPF
    • PHARMACOKINETICS IN HUMANS AND NONCLINICAL SPECIES
    • EFFECTS IN MODELS OF PULMONARY FIBROSIS
    • EFFECTS IN MODELS OF CARDIAC FIBROSIS
    • EFFECTS IN MODELS OF RENAL FIBROSIS
    • EFFECTS IN MODELS OF HEPATIC FIBROSIS
    • EFFECTS ON MEDIATORS OF FIBROSIS
    • EFFECTS IN CELL-BASED ASSAYS
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