Intratracheal Bleomycin Aerosolization: The Best Route of Administration for a Scalable and Homogeneous Pulmonary Fibrosis Rat Model?

Alexandre Robbe,Alexandre Legrand,Justine Carpentier,Denis Nonclercq,Anne-Emilie Declèves,Alexandra Tassin,Zita Léa Mekinda Ngono

doi:10.1155/2015/198418

Alexandre Robbe, Alexandre Legrand + Show 5 more

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https://doi.org/10.1155/2015/198418

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML) is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a severe form of fibrosing interstitial lung disease with unknown etiology and characterized by a progressive loss of lung function associated with dyspnea and cough
BLM Instillation Model Allowed a Gradual Fibrosis Preceded by an Inflammatory Phase
While original studies demonstrated the persistence of fibrosis for a few months, others described a resolution of the process beyond 28 days

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a severe form of fibrosing interstitial lung disease with unknown etiology and characterized by a progressive loss of lung function associated with dyspnea and cough. This heterogeneous pathology carries an invariable poor prognosis [1], with a median survival of less than three years from diagnosis. A great majority of those studies demonstrated a lack of efficacy or deleterious effects [2]. Therapeutic options remain limited, despite an increased and recent interest for new antifibrotic and anti-inflammatory agents such as pirfenidone or nintedanib, which have demonstrated efficacy in several clinical studies. Pirfenidone was further approved for medication in many countries [2]

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