Comparison between conventional and "clinical" assessment of experimental lung fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs.

Ex vivomicro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation

“…A recent study by JIN et al [24] used micro-CT (with ,44.25-mm spatial resolution) to investigate the therapeutic effects of rosiglitazone during BILF in mice; they reported beneficial changes in a qualitative radiological assessment, but did not provide a fully quantitative measure of fibrotic change. It is worth mentioning that the study by ASK et al [21] also investigated lung function (pressure-volume loops on mechanical ventilation) and demonstrated a strong correlation between lung stiffness and the degree of fibrosis on micro-CT, highlighting that lung function parameters are also a highly relevant end-point measure in fibrosis models.…”

“…Few studies, however, have addressed the use of micro-CT for evaluation of the degree of fibrotic change in murine models of lung fibrosis. Previous studies [21][22][23] used in vivo micro-CT to investigate fibrotic changes in the adenoviral TGF-b1 overexpression-induced or bleomycin models of lung fibrosis in rats or mice with associated voxel sizes of ,155 mm, 94 mm or 35 mm. These studies used different approaches to segment the tissue into either fibrotic [21] or aerated lung volumes [22], or used semiquantitative pathological scoring [23], but the utility of these approaches has not yet been validated with a drug intervention strategy.…”

“…Previous studies [21][22][23] used in vivo micro-CT to investigate fibrotic changes in the adenoviral TGF-b1 overexpression-induced or bleomycin models of lung fibrosis in rats or mice with associated voxel sizes of ,155 mm, 94 mm or 35 mm. These studies used different approaches to segment the tissue into either fibrotic [21] or aerated lung volumes [22], or used semiquantitative pathological scoring [23], but the utility of these approaches has not yet been validated with a drug intervention strategy. A recent study by JIN et al [24] used micro-CT (with ,44.25-mm spatial resolution) to investigate the therapeutic effects of rosiglitazone during BILF in mice; they reported beneficial changes in a qualitative radiological assessment, but did not provide a fully quantitative measure of fibrotic change.…”

Noninvasive Imaging of Experimental Lung Fibrosis

“…Serial micro-CT scanning generates quantitative datasets that can be reconstructed to assess the topographical distribution of lung fibrosis and quantitative evaluation of disease severity (7). The fibrotic lesions in current animal models of lung fibrosis are characterized by spatial heterogeneity.…”

“…Because three-dimensional reconstruction of micro-CT scans provides information of the entire thoracic cavity, micro-CT-based measurements are less likely to be influenced by the nonuniform distribution of lung fibrosis. Several micro-CT analysis protocols have been developed and validated for quantification of aerated lung volume (an inverse surrogate marker for pulmonary fibrosis) in mice and rats (3,5,7). A major challenge for quantification of aerated lung volume by micro-CT scans is correct segmentation of airspaces from intrapulmonary fibrotic tissues and from the surrounding extrapulmonary tissues.…”