title: Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230.
abstract: 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 MRI-assessed 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland; University of Basel, Biocenter, Basel, Switzerland;
authors.forename: Christine
authors.initials: C
authors.lastname: Egger
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Christelle
authors.initials: C
authors.lastname: Gérard
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Nella
authors.initials: N
authors.lastname: Vidotto
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Accart
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Catherine
authors.initials: C
authors.lastname: Cannet
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunbar
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland;
authors.forename: Bruno
authors.initials: B
authors.lastname: Tigani
authors.affiliation: Novartis Institutes for BioMedical Research, Preclinical Safety, Basel, Switzerland;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piaia
authors.affiliation: Novartis Institutes for BioMedical Research, Respiratory Diseases Department, Horsham, United Kingdom; and.
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
authors.affiliation: Novartis Institutes for BioMedical Research, Respiratory Diseases Department, Horsham, United Kingdom; and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jarman
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Department, Basel, Switzerland.
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Schmid
authors.affiliation: Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Basel, Switzerland; nicolau.beckmann@novartis.com.
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001761:Bleomycin; D013004:Somatostatin; C517782:pasireotide; D006909:Hydroxyproline
keywords: SOM230; bleomycin; compliance; elastance; fibrosis; imaging; magnetic resonance imaging (MRI); ultrashort echo time (UTE)