Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Daniels, Craig; Wilkes, Mark C.; Edens, Maryanne; Kottom, Ted J.; Murphy, Stephen J.; Limper, Andrew H.; Leof, Edward B.

doi:10.1172/jci200419603

Cited by 495 publications

(322 citation statements)

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“…Indeed, consistent with the data presented herein, imatinib mesylate has been shown to reduce the accumulation of ECM proteins in a model of pulmonary fibrosis. In addition, it reduced renal ECM accumulation in a model of unilateral obstructive nephropathy (11)(12)(13).…”

Section: Discussionmentioning

confidence: 94%

“…Imatinib mesylate is a small-molecule tyrosine kinase inhibitor that binds to the ATP-binding pocket of c-Abl and efficiently blocks its tyrosine kinase activity. Notably, c-Abl has recently been identified as an important downstream molecule in TGF␤ signaling (11)(12)(13). Using mouse embryonic fibroblasts deficient in c-Abl, Daniels et al demonstrated that c-Abl is crucial for the induction of ECM proteins by TGF␤ and that inhibition of c-Abl by imatinib mesylate reduced the synthesis of ECM components in vitro and in vivo in a lung fibrosis model (11).…”

mentioning

confidence: 99%

“…Notably, c-Abl has recently been identified as an important downstream molecule in TGF␤ signaling (11)(12)(13). Using mouse embryonic fibroblasts deficient in c-Abl, Daniels et al demonstrated that c-Abl is crucial for the induction of ECM proteins by TGF␤ and that inhibition of c-Abl by imatinib mesylate reduced the synthesis of ECM components in vitro and in vivo in a lung fibrosis model (11). Most interestingly, in addition to its effects on c-Abl, imatinib mesylate interferes with PDGF signaling by blocking the tyrosine kinase activity of PDGF receptors, and also inhibits the tyrosine kinase activity of the gene product of the protooncogene c-Kit, a transmembrane receptor for stem cell factor (14,15).…”

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confidence: 99%

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Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

362

273

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Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycininduced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF␤ and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

362

273

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“…), Cytokines (Interferon-β (Azuma, Li et al, 2005), Interferon-γ (Gurujeyalakshmi & Giri, 1995;Hyde, Henderson, Giri, Tyler, & Stovall, 1988;Okada, Sugie, & Aisaka, 1993), Interleukin (IL)-1beta (M. Yasui et al, 1991), IL-10 (Arai et al, 2000), IL-18 (Nakatani-Okuda et al, 2005), Keratinocyte growth factor (Deterding et al, 1997;Sugahara, Iyama, Kuroda, & Sano, 1998;Yi et al, 1996), Hepatocyte growth factor (Dohi, Hasegawa, Yamamoto, & Marshall, 2000;Mizuno, Matsumoto, Li, & Nakamura, 2005;Umeda et al, 2004;Yaekashiwa et al, 1997), Chemokine ligand (CXCL)-10 (Tager et al, 2004),CXCL11 (Burdick et al, 2005), CD (cluster of differentiation)-36 (Yehualaeshet et al, 2000) etc. ), Cytokine antibodies (Transforming growth factor-β (Giri, Hyde, & Hollinger, 1993), Tumor necrosis factor-α (Fichtner-Feigl, Strober, Kawakami, Puri, & Kitani, 2006;Fujita et al, 2003;Piguet & Vesin, 1994), Connective tissue growth factor (Matsuoka et al, 2002), IL-12 , IL-13 (Fichtner-Feigl, Strober, Kawakami, Puri, & Kitani, 2006), Platelet derived growth factor (Aono et al, 2005;Chaudhary, Schnapp, & Park, 2006;Daniels et al, 2004;Yoshida et al, 1999), Vascular endothelial growth factor (Hamada et al, 2005), CCR-1 (Tokuda et al, 2000), CCR-3 (Huaux et al, 2005), CCL-11 (Huaux et al, 2005), CD-11 (Piguet, Rosen, Vesin, & Grau, 1993), MCP-1 etc. ), Chinese herbs (Feitai (Gong et al, 2004;Gong et al, 2005;…”

Section: Drug Intervention Studies In the Bleomycin Modelmentioning

confidence: 99%

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

822

724

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Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

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“…In contrast, the structurally divergent Smad6 and Smad7 inhibit TGF-β signaling (inhibitory Smads). Recently, it has become increasingly apparent that TGF-β not only activates Smads, but also signals through Smad-independent pathways [321] that may involve c-Abl [322], p21-activated kinase-2 (PAK2) [323], TGF-β Activated Kinase (TAK)-1 [324], and p38 MAPK [325].…”

Section: Tgf-β Signaling Pathways In Cardiac Injurymentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Cited by 495 publications

References 46 publications

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

The immune system and cardiac repair

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