Indocyanine-enhanced mouse model of bleomycin-induced lung fibrosis with hallmarks of progressive emphysema

Andrea Grandi, Erica Ferrini, Laura Mecozzi, Roberta Ciccimarra, Matteo Zoboli, Ludovica Leo, Zahra Khalajzeyqami, Alex Kleinjan, Clemens W.G.M. Löwik, Gaetano Donofrio, Gino Villetti, Franco Fabio Stellari*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)
33 Downloads (Pure)

Abstract

The development of new drugs for idiopathic pulmonary fibrosis strongly relies on preclinical experimentation, which requires the continuous improvement of animal models and integration with in vivo imaging data. Here, we investigated the lung distribution of bleomycin (BLM) associated with the indocyanine green (ICG) dye by fluorescence imaging. A long-lasting lung retention (up to 21 days) was observed upon oropharyngeal aspiration (OA) of either ICG or BLM þ ICG, with significantly more severe pulmonary fibrosis, accompanied by the progressive appearance of emphysema-like features, uniquely associated with the latter combination. More severe and persistent lung fibrosis, together with a progressive air space enlargement uniquely associated with the BLM þ ICG group, was confirmed by longitudinal micro-computed tomography (CT) and histological analyses. Multiple inflammation and fibrosis biomarkers were found to be increased in the bronchoalveolar lavage fluid of BLM- and BLM þ ICG-treated animals, but with a clear trend toward a much stronger increase in the latter group. Similarly, in vitro assays performed on macrophage and epithelial cell lines revealed a significantly more marked cytotoxicity in the case of BLM þ ICG-treated mice. Also unique to this group was the synergistic upregulation of apoptotic markers both in lung sections and cell lines. Although the exact mechanism underlying the more intense lung fibrosis phenotype with emphysema-like features induced by BLM þ ICG remains to be elucidated, we believe that this combination treatment, whose overall effects more closely resemble the human disease, represents a valuable alternative model for studying fibrosis development and for the identification of new antifibrotic compounds.

Original languageEnglish
Pages (from-to)L211-L227
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume324
Issue number2
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Grants:
This study was fully supported by Chiesi Farmaceutici S.p.A.

Publisher Copyright:
© 2023 American Physiological Society. All rights reserved.

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