Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats

Sugahara, Kazuhiro; Iyama, Ken Ichi; Kuroda, Marcelo J.; Sano, Kimihiko

doi:10.1002/(sici)1096-9896(199809)186:1<90::aid-path137>3.0.co;2-x

Cited by 91 publications

(23 citation statements)

References 23 publications

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“…We were particularly interested in KGF because of work from our group as well as other investigators who have reported that KGF can reduce lung injury in small animal models of pulmonary edema. Recombinant KGF pretreatment reduced mortality following intra-tracheal instillation of hydrochloric acid (37), bleomycin (38), hyperoxia (39) and Pseudomonas aeruginosa (40). In models of acute permeability edema such as ␣-naphthylthiourea (41), P. aeruginosa (40) or ventilator-induced lung injury (42), KGF reduced lung edema and bronchoalveolar lavage protein levels.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

Lee¹,

Fang

Gupta

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

642

560

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Section: Discussionmentioning

confidence: 99%

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

Lee¹,

Fang

Gupta

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

642

560

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“…Li, Azuma, Takahashi et al, 2002) etc. ), 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.…”

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

796

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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“…FGF2 is required for epidermal and epithelial repair after injury to the skin and retina (40), and other FGFs, such as the FGFR2b ligands, FGF7 and FGF10, promote lung epithelial proliferation and improve recovery of epithelial barrier function after injury (41,42). It is not known, however, whether this effect is limited to FGF7 and FGF10, or whether endogenous FGF2 is required.…”

Section: Fgf2 Is Required For Recovery Of Epithelium In Response To Bmentioning

confidence: 99%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

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Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats

Cited by 91 publications

References 23 publications

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

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

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

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