Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

Ashcroft, T; Simpson, Judy M.; Timbrell, V.

doi:10.1136/jcp.41.4.467

Cited by 1,354 publications

(1,016 citation statements)

References 3 publications

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“…For the assessment of fibrosis several common methods were used, including semi-quantitative histological analysis, sometimes based on the scoring system by Ashcroft (Ashcroft, Simpson, & Timbrell, 1988), and quantification of hydroxyproline and/or collagen content. Bronchoalveolar lavage fluid (BALF) was often analyzed for changes in total cell count, differential count of leucocytes, and measurement of tumor necrosis factor alpha (TNF) α or TGFβ levels.…”

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

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Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

828

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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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

828

724

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“…Four axial sections of the distal left lung were stained with Picro Sirius Red (PS Red) and 20 microscopically fields were examined for pulmonary fibrosis by three blinded investigators. Each field was individually assessed for the severity of interstitial fibrosis using Ashcroft's semi quantitative grading previously described (Ashcroft, Simpson, & Timbrell, 1988). Immunohistochemistry was carried out using antibody to αSMA (M0851, Dako Canada Inc., Mississaugua, ON, Canada), phospho-Smad2 Cat no 3101 (Cell Signaling Technology, Inc, Danvers, MA, USA) or TGF beta Receptor I (V-22) Cat No sc-398 (Santa Cruz Biotechnology Inc, Santa Cruz, CA.…”

Section: Histologymentioning

confidence: 99%

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

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Bonniaud

Maaß

et al. 2008

The International Journal of Biochemistry & Cell Biology

154

114

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Tissue repair is a well orchestrated biological process involving numerous soluble mediators, and an imbalance between these factors may result in impaired repair and fibrosis. Transforming growth factor (TGF) β is a key profibrotic element in this process and it is thought that its three isoforms act in a similar way. Here, we report that TGF-β3 administered to rat lungs using transient overexpression initiates profibrotic effects similar to those elicited by TGF-β1, but causes less severe and progressive changes. The data suggest that TGF-β3 does not lead to inhibition of matrix degradation in the same way as TGF-β1, resulting in non-fibrotic tissue repair. Further, TGF-β3 is able to downregulate TGF-β1 induced gene expression, suggesting a regulatory role of TGF-β3. TGF-β3 overexpression results in an upregulation of Smad proteins similar to TGF-β1, but is less efficient in inducing the ALK 5 and TGF-β type II receptor (TβRII). We provide evidence that this difference may contribute to the progressive nature of TGF-β1 induced fibrotic response, in contrast to the limited fibrosis observed following TGF-β3 overexpression. TGF-β3 is important in "normal wound healing", but is outbalanced by TGF-β1 in "fibrotic wound healing" in the lung.

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“…The sections were then scored to determine the extent of inflammation in each section. The scoring system was based on that described by Aschroft et al 35 Lungs were analysed at high power ( Â 1000 original magnification) and five random fields per lobe were analysed by two independent observers in a blinded fashion. Each field was ascribed a score of 0-3: 0, represents normal lung with no inflammation; 1, mild interstitial infiltrate; 2, interstitial inflammation with alveolar exudates; 3, complete obliteration of the alveoli.…”

Section: Histological Assessment Of Lungs For Inflammationmentioning

confidence: 99%

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo

et al. 2003

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There is currently an urgent need to develop efficient genedelivery systems for the lung that are free of inflammatory effects. The LID vector is a synthetic gene delivery system, comprised of lipofectin (L), an integrin-targeting peptide (I) and DNA (D) that has previously been shown to have high transfection efficiency in the lung. We have assessed the effect of alternative methods of complex preparation on structural features of the complex, levels and duration of reporter gene expression and the host response to the LID vector. We have demonstrated that making the complex in water affects the structure of the LID complexes making them smaller and more stable with a more cationic surface charge than complexes prepared in phosphate-buffered saline (PBS). When the LID vector was constituted in water and instilled intratracheally into the lungs of mice there was a 10-fold increase in luciferase activity compared with preparation in PBS. Furthermore, luciferase activity was still evident 1 week following vector instillation. This enhancement may be because of altered complex structure, although effects of the hypotonic vector solution on the lung cannot be excluded. The inflammatory effects of instilling the LID vector in water were minimal, even after three administrations of the LID vector, with only mild alterations in cytokine and broncho-alveolar lavage fluid (BALF) cell profiles. These results demonstrate that the LID vector can generate high, and prolonged, levels of gene expression in the lung from small quantities of DNA and that careful attention to synthetic polyplex structure may be important to optimize efficiency of gene expression in vivo.

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Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

Cited by 1,354 publications

References 3 publications

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

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

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo

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