A mouse model of progressive lung fibrosis with cutaneous involvement induced by a combination of oropharyngeal and osmotic minipump bleomycin delivery

Am J Physiol Lung Cell Mol Physiol. 2024 Apr 23. doi: 10.1152/ajplung.00408.2023. Online ahead of print.ABSTRACTSystemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) lacks curative pharmacological treatments, thus necessitating effective animal models for candidate drug discovery. Existing Bleomycin (BLM)-induced SSc-ILD mouse models feature spatially limited pulmonary fibrosis, spontaneously resolving after 28 days. Here, we present an alternative BLM administration approach in female C57BL/6 mice, combining oropharyngeal aspiration (OA) and subcutaneous mini-pump delivery (pump) of BLM to induce a sustained and more persistent fibrosis, while retaining stable skin fibrosis. A dose-finding study was performed with BLM administered as 10 µg (OA) +80 mg/kg (pump) (10+80), 10+100 and 15+100. Forty-two days after OA, micro-CT imaging and histo-morphometric analyses showed that the 10+100 and 15+100 treatments induced significant alterations in lung micro-CT-derived readouts, Ashcroft Score, and more severe fibrosis grades compared to saline controls. Additionally, a marked reduction in hypodermal thickness was observed in the 15+100 group. A time-course characterization of the BLM 15+100 treatment at days 28, 35, and 42, including longitudinal micro-CT imaging, revealed progressing alterations in lung parameters. Lung histology highlighted a sustained fibrosis accompanied by a reduction in hypodermis thickness throughout the explored time-window, with a time-depende...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Source Type: research