Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis

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Abstract

Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5 mg/kg/day) was administered on days −7, −6, −5, −2, −1, 0 in the nostrils of male mice. PT100 (40 μg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1–14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P<0.001, N=24) was found between the volumes of BLM-induced lesions detected in vivo by MRI and the collagen content determined histologically (picrosirius staining). FAP was overexpressed in the lungs of BLM-challenged mice. Upon PT100 treatment, FAP expression was reduced. Significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs of PT100- compared to vehicle-treated mice were also revealed by qRT-PCR. The IBA-1 level determined histologically was higher in the lungs of PT100- compared to vehicle-treated mice. Taken together, these observations suggest that treatment with PT100 in this murine model of pulmonary fibrosis had an anti-fibro-proliferative effect and increased macrophage activation.

Graphical abstract

Lung MRI of spontaneously breathing mice to assess the effect of the fibroblast activation protein inhibitor, PT100. Axial multislice images through the chest of a saline-challenged, vehicle-treated animal and two bleomycin (BLM)-challenged mice, treated either with vehicle or PT100 from day 1 until the end of the study. Images were acquired at day 14 after last saline or BLM dosing. Vessels are indicated by white arrows, and BLM-induced lesions by red arrows.

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