Bleomycin-Induced Chronic Lung Damage Does Not  Resemble Human Idiopathic Pulmonary Fibrosis

Borzone, Gisella; Moreno, Rodrigo; Urrea, Rodrigo Frías; Meneses, Manuel; Oyarzún, M; Lisboa, Cármen

doi:10.1164/ajrccm.163.7.2006132

Cited by 145 publications

(109 citation statements)

References 13 publications

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“…In agreement with previous reports [4,23,28], a significant suppression of body weight gain was observed in the 4.5 and 6.0 mg/kg groups. However, there were no deaths on the day of dosing or during the 3-week observation period.…”

Section: Discussionsupporting

confidence: 93%

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

et al. 2004

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Abstract:In order to ensure a widespread distribution in the lung and to avoid the effect of anesthesia, bleomycin at a total dose of 4.5 or 6.0 mg/kg was administered in four divided doses (0.5 ml/kg/time) at intervals of 2 h to male rats via a catheter (tracheotomy tube) without anesthesia. In comparison to vehicle (saline) controls, bleomycin-treated rats showed a significant suppression of body weight gain that was observed transiently at 4.5 mg/kg and continuously (throughout the 3-week observation period) at 6.0 mg/kg. Histopathologically, interstitial pneumonitis, thickening of alveolar walls, thickening of pulmonary arterial walls, foamy cells in alveoli, and hemorrhage were observed in both 4.5 and 6 mg/kg groups, and also emphysema in the 6 mg/kg group. Both groups exhibited a significant decrease in the partial pressure of arterial oxygen (PaO 2 ) and a significant increase in alveolar-arterial oxygen tension difference (AaDO 2 ), and a significant increase in erythrocyte count was observed in the 6 mg/kg group. Furthermore, both treated groups showed a significant increase in the ratio of the right ventricular weight versus left ventricle plus septum weights. The significant increase in erythrocyte count might have been caused by diffusion disturbance and ventilation-perfusion imbalance due to the pulmonary damage. These findings suggest that the present experimental method will be useful for clarification of the pulmonary damage induced by bleomycin in rats. Key words: bleomycin, catheter, diffusion disturbance, erythrocyte count, ventilationperfusion imbalance the precise mechanisms involved in the induction of this disease have not been clarified completely. In rodents, a single intratracheal administration under anesthesia is frequently used for preparing an animal model [7,10,23,26,32], but the extent and severity of pulmonary damage caused by bleomycin varies considerably depending on the attainability of the drug solution [16]. Furthermore, anesthesia itself causes respiratory and

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Section: Discussionsupporting

confidence: 93%

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

et al. 2004

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“…This model has been highly criticized as a representative model of human IPF. 27 However, to date, it represents the most used experimental reproduction of the disease. All our mice developed extensive lung damage after BLM treatment, with a prevalent inflammatory component already evident 48 h after injury.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Lunardi

Villano

Perissinotto

et al. 2011

Laboratory Investigation

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SERPIN B3/B4, members of the serpin superfamily, are fundamental for the control of proteolysis through a known inhibitory function of different proteases. Several studies have documented an important role of SERPIN B3 in the modulation of inflammation, programmed cell death and fibrosis. To confirm the role of SERPIN B3 in lung fibrosis and overall investigate its influence on epithelial dysfunction, a stratified controlled trial randomly assigning bleomycin (BLM) treatment was performed on both SERPIN B3 transgenic (TG) and wild-type (WT) mice. TG and WT animals were killed 48 h (group T48 h) and 20 days (group T20d) after BLM treatment. Lung fibrosis was assessed by histology and hydroxyproline measurement. Architectural remodeling, inflammation, epithelial apoptosis and proliferation were quantified. Moreover, the profibrogenetic cytokine transforming growth factor (TGF)-b, cathepsin K, L and S were also investigated. No significant differences were observed between TG and WT mice of group T48 h in any parameters. In group T20d, less inflammation and a significant increase in epithelial proliferation were detected in treated TG than WT mice despite a similar apoptotic index, thus resulting in a different apoptosis/proliferation imbalance with a significant gain of epithelial proliferation. Moreover, TG mice showed higher TGF-b expression and more extended fibrosis. General linear model analysis, applied on morphological data, showed that interaction between SERPIN B3 expression and treatment was mainly significant for fibrosis. This study provides in vivo evidence for a role of SERPIN B3 in inhibiting inflammation and favoring epithelial proliferation with increased TGF-b secretion and thus the likelihood of consequent fibrogenesis.Laboratory Investigation (2011) 91, 945-954;

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“…The trachea was exposed after a small cervical skin incision and separation of strap muscles, and punctured with a 26-gauge needle for the administration of bleomycin sulphate (BLM; Bleocin-S, Nippon Kayaku Co., Ltd, Tokyo, Japan) (Borzone et al, 2001). A single dose of 2.5 U/kg BLM dissolved in 0.3 mL PBS was instilled by intratracheal (IT) injection.…”

Section: Experimental Model and Experimental Groupsmentioning

confidence: 99%

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

et al. 2012

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Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-infl ammatory properties of statins. The purpose of this study was to evaluate the anti-infl ammatory eff ect of simvastatin on bleomycin (BLM)-induced pulmonary fi brosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buff ered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The eff ect of simvastatin on pulmonary fi brosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-β1 levels in bronchoalveolar lavage (BAL) fl uid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused signifi cant change in BAL fl uid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no eff ect on cytokine levels, HD signifi cantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no eff ect on a BLMinduced pulmonary fi brosis model, while the high dose caused partial improvement in profi brotic cytokine levels.

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Bleomycin-Induced Chronic Lung Damage Does Not Resemble Human Idiopathic Pulmonary Fibrosis

Cited by 145 publications

References 13 publications

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

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