Administration of Bleomycin via the Oropharyngeal Aspiration Route Leads to Sustained Lung Fibrosis in Mice and Rats as Quantified by UTE-MRI and Histology

Egger, Christine; Cannet, Catherine; Gérard, Christelle; Jarman, Edward J.; Járai, Gábor; Feige, A Hiou; Suply, Thomas; Micard, Arthur; Dunbar, Andrew; Tigani, Bruno; Beckmann, Nicolau

doi:10.1371/journal.pone.0063432

Cited by 103 publications

(93 citation statements)

References 49 publications

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“…Sprague-Dawley rats were lightly anesthetized with 2.5% isoflurane (Abbott, Cham, Switzerland) delivered in a plastic box, and bleomycin hydrochloride (2 or 3 mg/kg; Teva, Basel, Switzerland) in 100 l of saline (0.9%) or vehicle [100 l of saline (0.9%)] was administered via oropharyngeal aspiration with a micropipette as described earlier (16). Mice were lightly anesthetized with 2% isoflurane delivered in a plastic box and bleomycin hydrochloride (0.1 mg/kg) in 40 l of saline (0.9%) or vehicle [40 l of saline (0.9%)] was delivered via oropharyngeal aspiration (16). The procedure was performed six times consecutively, once daily.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, target identification and development of therapeutics against pulmonary fibrosis are challenging. The use of magnetic resonance imaging (MRI) to noninvasively follow the course of lung injury induced by bleomycin administration to mice (3,16) and rats (2,16,24,25) has been reported earlier. The ability of MRI to noninvasively quantify lung injury in bleomycin-treated animals facilitates in vivo pharmacological studies in the model.…”

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confidence: 99%

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Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230

Egger

Gérard

Vidotto

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230. Am J Physiol Lung Cell Mol Physiol 306: L1064 -L1077, 2014. First published April 11, 2014 doi:10.1152/ajplung.00027.2014.-Idiopathic pulmonary fibrosis is a progressive and lethal disease, characterized by loss of lung elasticity and alveolar surface area, secondary to alveolar epithelial cell injury, reactive inflammation, proliferation of fibroblasts, and deposition of extracellular matrix. The effects of oropharyngeal aspiration of bleomycin in Sprague-Dawley rats and C57BL/6 mice, as well as of intratracheal administration of ovalbumin to actively sensitized Brown Norway rats on total lung volume as assessed noninvasively by magnetic resonance imaging (MRI) were investigated here. Lung injury and volume were quantified by using nongated or respiratory-gated MRI acquisitions [ultrashort echo time (UTE) or gradient-echo techniques]. Lung function of bleomycin-challenged rats was examined additionally using a flexiVent system. Postmortem analyses included histology of collagen and hydroxyproline assays. Bleomycin induced an increase of MRIassessed total lung volume, lung dry and wet weights, and hydroxyproline content as well as collagen amount. In bleomycin-treated rats, gated MRI showed an increased volume of the lung in the inspiratory and expiratory phases of the respiratory cycle and a temporary decrease of tidal volume. Decreased dynamic lung compliance was found in bleomycin-challenged rats. Bleomycin-induced increase of MRI-detected lung volume was consistent with tissue deposition during fibrotic processes resulting in decreased lung elasticity, whereas influences by edema or emphysema could be excluded. In ovalbumin-challenged rats, total lung volume quantified by MRI remained unchanged. The somatostatin analog, SOM230, was shown to have therapeutic effects on established bleomycin-induced fibrosis in rats. This work suggests MRI-detected total lung volume as readout for tissue-deposition in small rodent bleomycin models of pulmonary fibrosis.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230

Egger

Gérard

Vidotto

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We used a BL-PF model by delivering bleomycin via oropharyngeal aspiration as previously defined (69), with slight modifications. Briefly, mice were anesthetized with intraperitoneal injection of ketamine/xylazine (84 mg/ml ketamine/1 ml/kg xylazine) and placed on a surgery board in the supine position at an angle of 45°, with the head immobilized by an elastic band across the upper incisors.…”

Section: Cnr1mentioning

confidence: 99%

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Çınar¹,

Gochuico²,

Iyer³

et al. 2017

JCI Insight

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“…Tissue histology was performed on three transverse sections cut through the left lung, dehydrated through ascending grades of ethanol and embedded in paraffin wax. Sections were stained with hematoxylin and eosin (H&E) stain to assess general morphology [26].…”

Section: Measurement Of Inflammationmentioning

confidence: 99%

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Patel

Woods

Riffo‐Vasquez

et al. 2016

Journal of Controlled Release

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Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50 nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of 111 In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p < 0.001). When normalised to the delivered lung dose, the clearance kinetics of 111 In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5 ± 0.9 h (R 2 = 0.995) and 10.6 ± 0.3 h (R 2 = 1.000) for healthy and inflamed lungs respectively (n = 3). In contrast, 111 In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20 min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.

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Administration of Bleomycin via the Oropharyngeal Aspiration Route Leads to Sustained Lung Fibrosis in Mice and Rats as Quantified by UTE-MRI and Histology

Cited by 103 publications

References 49 publications

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

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