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Therapeutic effects of obeticholic acid (OCA) treatment in a bleomycin-induced pulmonary fibrosis rat model

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Abstract

Purpose

We recently demonstrated a protective effect of the farnesoid X receptor agonist obeticholic acid (OCA) in rat models of bleomycin-induced pulmonary fibrosis (PF). Aim of the present study was to investigate whether the positive effects of OCA treatment are apparent also on ongoing bleomycin-induced PF, i.e., after 2 weeks of bleomycin administration.

Methods

Bleomycin-induced PF rats were treated 2 weeks after bleomycin administration with OCA or pirfenidone for two additional weeks. Pulmonary function test was performed at 2 and 4 weeks in all experimental groups. At the same time points, lung morphological features and mRNA expression profile of genes related to fibrosis, inflammation and epithelial–mesenchymal transition were also assessed.

Results

After 2 weeks, bleomycin significantly increased the pressure at the airway opening (PAO), a functional parameter related to fibrosis-induced lung stiffness, and induced diffuse lung interstitium fibrosis, with upregulation of inflammation (IL1β, MCP1) and tissue remodeling (COL1A1, COL3A1, ET1, MMP7, PDGFa, αSMA, SNAI1) markers. At week four, a further increase of lung fibrosis and PAO was observed, accompanied by upregulation of extracellular matrix-related mRNA expression. OCA administration, even after the establishment of PF, significantly improved pulmonary function, normalizing PAO, and reverted the bleomycin-induced lung alterations, with significant reduction of markers of inflammation (CD206, COX2, HIF1, IL1β, MCP1), epithelial proliferation (CTGF, PDGFa) and fibrosis (COL1A1, COL3A1, ET1, FN1, MMPs, αSMA, SNAIs, TGFβ1, TIMPs). Results with OCA were similar or superior to those obtained with pirfenidone.

Conclusions

In conclusion, our results demonstrate a significant therapeutic effect of OCA in already established PF.

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Acknowledgements

This study has been supported by a scientific grant from Intercept Pharmaceuticals (New York, NY).

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Authors and Affiliations

  1. Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Viale Pieraccini, 6, 50139, Florence, Italy

    P. Comeglio, I. Cellai, C. Corno, M. Maggi & L. Vignozzi

  2. Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of NEUROFARBA, University of Florence, Florence, Italy

    S. Filippi

  3. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    E. Sarchielli, A. Morelli, A. Pini & G. B. Vannelli

  4. Intercept Pharmaceuticals, New York, NY, USA

    L. Adorini

  5. I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy

    M. Maggi & L. Vignozzi

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  1. P. Comeglio
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Correspondence to L. Vignozzi.

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Conflict of interest

PC, SF, ES, AM, IC, CC, AP, GBV, MM and LV have no conflicts of interest. LA is a scientific consultant for Intercept Pharmaceuticals.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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This article does not contain any studies with human participants performed by any of the authors.

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Comeglio, P., Filippi, S., Sarchielli, E. et al. Therapeutic effects of obeticholic acid (OCA) treatment in a bleomycin-induced pulmonary fibrosis rat model. J Endocrinol Invest 42, 283–294 (2019). https://doi.org/10.1007/s40618-018-0913-1

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  • DOI: https://doi.org/10.1007/s40618-018-0913-1

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