Repeated instillations of bleomycin in male mice induce a perivascular remodeling at distance of fibrotic areas in the context of progressive pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the archetypal form of progressive pulmonary fibrosis (PPF), as well as being the most common and severe type of interstitial lung disease. IPF is characterized by progressive, diffuse interstitial remodeling, stiffening of the lung parenchyma and is also most often associated with pulmonary hypertension (PH), which significantly impacts the clinical course and outcome of the disease. To improve targeted therapeutic options and survival predictions, as well as offering an overall better understanding of the disease, researchers need models that best reflect the characteristics observed in patients and allow the study of comorbidities associated with pulmonary fibrosis. Chronic pulmonary fibrosis was induced in male C57BL/6 mice through intratracheal instillation (ITI) of 3 low-doses of bleomycin (BLM) every 2 weeks. Mice were sacrificed 15 or 90 days after the last ITI. Clinical follow-up and histological analysis were performed to study lung and perivascular remodeling. Our results suggest that fractionated bleomycin instillation generates a persistent and progressive pulmonary fibrosis in mice. This is associated with collagen remodeling in the perivascular space outside fibrotic areas. We hypothesize that this remodeling, accompanied by a mild but significant increase in pulmonary artery media thickness, could be a precursor to pulmonary fibrosis-associated hypertension. These results suggest that this model could improve our understanding of pulmonary remodeling and vascular lesions in the early stages of pulmonary fibrosis.