Pharmacologic Differentiation of Inflammation and Fibrosis in the Rat Bleomycin Model

Chaudhary, Nveed; Schnapp, Andreas; Park, John E.

doi:10.1164/rccm.200505-717oc

Cited by 301 publications

(279 citation statements)

References 31 publications

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“…The initial response to BLM instillation is the induction of an acute inflammatory response characterized by gross perivascular infiltration and edema (1,28), observed one week following treatment, as has been shown in the present study. In experiments performed by Lazenby et al (1), mononuclear cells were present around large airways and vessels and no evidence of fibrotic development was observed 48 hours after BLMtreatment.…”

Section: Discussionsupporting

confidence: 79%

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

Karmouty‐Quintana

Cannet

Zurbruegg

et al. 2007

Magnetic Resonance Imaging

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Purpose:To apply proton magnetic resonance imaging (MRI) techniques to assess noninvasively and in spontaneously breathing rats, structural changes following a single intratracheal administration of bleomycin (BLM). Materials and Methods:Rats were scanned by MRI prior to BLM or vehicle administration and at six hours, 24 hours, week 1, and at weeks 2, 3, 6, and 8 after treatment. Bronchoalveolar lavage (BAL) fluid and histological analyses were performed at 24 hours, and at weeks 1 and 8 (histology only).Results: Prominent MRI fluid signals were detected in the lungs of BLM-treated rats one week after challenge. These signals correlated with increased inflammatory parameters in BAL fluid and with marked perivascular and parenchymal infiltration with inflammatory cells in histological slices. At week 2 the MRI signals due to edema resolved, but nevertheless an increase in MRI signal intensity from the lung parenchyma was apparent. In some areas of the right lung the MRI signal intensity in the parenchyma decreased between weeks 2 and 8. These observations were in line with histology demonstrating collagen deposition and atelectasis (hallmarks of fibrosis) at week 1 and a partial recovery of the lung parenchyma at week 8. Conclusion:The data demonstrate the ability of proton MRI to detect BLM-induced lung fibrosis as well as the acute inflammatory response caused by the agent.

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Section: Discussionsupporting

confidence: 79%

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

Karmouty‐Quintana

Cannet

Zurbruegg

et al. 2007

Magnetic Resonance Imaging

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“…This happens by chelation of metal ions, and reaction of the formed pseudoenzyme with oxygen, which leads to production of DNA-cleaving superoxide and hydroxide free radicals (Claussen & Long, 1999). An overproduction of reactive oxygen species can lead to an inflammatory response causing pulmonary toxicity, activation of fibroblasts and subsequent fibrosis (Chaudhary, Schnapp, & Park, 2006;Grande NR, 1998). Bleomycin hydrolase, a bleomycin-inactivating enzyme, critically influences the effects of this drug on different tissues.…”

Section: Bleomycinmentioning

confidence: 99%

“…This is important in order to distinguish between anti-inflammatory and antifibrotic drug effects, as the interpretation of drug effects is crucially dependent on timing of compound administration. Compounds administered during the early phase may predominantly act as anti-inflammatory agents and should be considered as "preventive treatment", whereas "true" antifibrotic agents might be effective irrespective of timing, particularly if administered during the "fibrotic" phase of the model (Chaudhary, Schnapp, & Park, 2006). In the vast majority of the reviewed studies, the compound was given as preventive treatment, thus confounding the designation as anti-inflammatory or anti-fibrotic.…”

Section: Drug Intervention Studies In the Bleomycin Modelmentioning

confidence: 99%

“…), 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%

“…), Immunosuppressants (Cyclosporin-A (Lossos, Or, Goldstein, Conner, & Breuer, 1996), Rapamycin analogue SDZ RAD (Simler et al, 2002)), Corticosteroids (Dexamethasone (F. Chen et al, 2006;Dik et al, 2003;H. P. Li, Li, He, Yi, & Kaplan, 2004), Methylprednisolone (Phan, Thrall, & Williams, 1981), Prednisolone (Chaudhary, Schnapp, & Park, 2006;Entzian et al, 1998) 1986) etc. ), and Pirfenidone (Ammar et al, 2006;Gurujeyalakshmi, Hollinger, & Giri, 1999;Iyer, Gurujeyalakshmi, & Giri, 1999;Iyer, Hyde, & Giri, 2000;Iyer, Margolin, Hyde, & Giri, 1998;Iyer et al, 1995;Kakugawa et al, 2004;Mansoor, Chen, Schelegle, & Giri, 1999;Schelegle, Mansoor, & Giri, 1997).…”

Section: Drug Intervention Studies In the Bleomycin Modelmentioning

confidence: 99%

See 2 more Smart Citations

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

793

714

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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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Mouse Models of Bleomycin‐Induced Pulmonary Fibrosis

2008

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Pulmonary fibrosis is a component of many interstitial lung diseases, including idiopathic pulmonary fibrosis, a chronic, progressive disease for which there is currently no effective therapy. Bleomycin has been widely used in rodents to model pulmonary fibrosis for the study of mechanisms involved in fibrogenesis and for evaluation of potential therapies. Bleomycin induces DNA strand breaks, resulting in pulmonary inflammation, injury, and subsequent interstitial fibrosis. This unit describes methods for delivering bleomycin, either directly into the lung or systemically, to create models of pulmonary fibrosis in rodents. Also described is a rapid and easy procedure for measuring lung collagen content to quantify the severity of fibrosis.

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Pharmacologic Differentiation of Inflammation and Fibrosis in the Rat Bleomycin Model

Abstract: The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.

Cited by 301 publications

References 31 publications

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

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

Mouse Models of Bleomycin‐Induced Pulmonary Fibrosis

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