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

Abstract

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.

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging

“…A similar increase in total lung volume was also observed in other lung disease models, such as the bleomycininduced lung fibrosis model 43 and pulmonary cryptococcosis model. This indicates that total volume changes are not specifically related to the development of a pulmonary fungal infection.…”

Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

“…However, in the present study hydroxyproline method would not allow to pick up subtle fibrotic alterations induced in the alveolar parenchyma [25]. Considering the available histological digital imaging methods they allow an overall quantification of collagen content in the alveolar parenchyma, bronchi and vessels [12, 14] but would not allow to quantify the distribution of collagen content restricted to fibrous and non-fibrous regions of the alveolar parenchyma in view of its correlation with density indexes.…”

“…Hounsfield unit (HU) histograms were obtained for left and right lungs using bins of 10-HU width. In the absence of a well-established gold standard to quantify fibrotic changes in rodents with micro-CT and to avoid relying on an arbitrary threshold to identify fibrotic regions [14,15] the HU corresponding to the peak of the HU-histogram for the segmented pixels were used as a measure of the progression of fibrosis. Total lung volume was also computed.…”

“…Several methods are currently used and considered as end-point measures in BLM-induced lung fibrosis in mice as micro-computed tomography (micro-CT), magnetic resonance imaging (MRI), gene expression analysis, biochemical analysis (hydroxyproline), blood biomarkers and lung function measurements [8–18]. Quantification of the severity of fibrosis is also accessed by means of histological methods based either on grading score [10, 19–24] or by digital imaging analysis [10, 12, 14, 25–27]. Histological scoring has been developed by assigning numerical scores in relationship with the amount of fibrosis in histological samples.…”

“…Digital imaging analysis is also used to quantify pulmonary morphological changes elicited by BLM-induced fibrosis. Most of the established digital imaging analyses evaluate the severity of BLM-induced fibrosis by quantifying collagen content stained by picrosirius red or to a lesser extent Masson trichrome or even more selectively by immunostaining [12, 14, 25–31]. The expression of collagen is determined from the ratio of the stained area versus the total area of the lung section.…”