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

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.

Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

“…Semi quantitative evaluation of pathology was based on the following scoring system: 0—intact lung; 1—increased cellularity; 2—granuloma formation; 3—granulomas with central necrosis; 4—large coalescent lesions with necrosis; 5—partial liquefaction; 6—extensive liquefaction; 7—cavity. Similarly, the extent of fibrosis was scored using modified Ashcroft scale: 0—normal lung (no fibrosis); 1—minimal fibrous thickening of alveolar or bronchiolar vessels; 2—moderate thickening of walls without obvious damage to lung architecture; 3—Increased fibrosis with definite damage to lung structure and formation of fibrous bands or small fibrous masses; 4—large fibrous areas; 5—total fibrous obliteration of the field ( Hubner et al, 2008 , Robbe et al, 2015 ). The number and size of granulomatous lesions in the Mtb-infected rabbit lung sections were enumerated by morphometric measurements using Sigmascan Pro software (Systat Softwares, Inc., CA).…”

Use of animal models in IPF research

“…and due to repeated micro-injuries [59]. Models that use repeated smaller insults that result in a progressive development of fibrosis such described elsewhere [3][4][5][6] [52,85,86] can be used in animal models to assess levels of pulmonary fibrosis.…”

Bleomycin Revisited: A Direct Comparison of the Intratracheal Micro-Spraying and the Oropharyngeal Aspiration Routes of Bleomycin Administration in Mice

“…However, intratracheal (IT) administration of a single BLM dose, resulting in bronchiolocentric fibrotic patches, has become the method of choice ( 3 ). Furthermore, the IT delivery of BLM through a microspray aerosolizer ( 8 ) has been shown to yield more reproducible results and more homogenous distribution of fibrotic lesions than IT instillation/injection ( 9 ). Following the example of other drugs and agents ( 10 – 13 ), an alternative way of administering BLM in the trachea, namely oropharyngeal aspiration (OA), has been recently introduced ( 14 , 15 ).…”