title: Anti-fibrotic effects of chronic treatment with the selective FXR agonist obeticholic acid in the bleomycin-induced rat model of pulmonary fibrosis.
abstract: Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated. Lung function was assessed by measuring airway resistance to inflation. In the acute phase (7days), bleomycin promoted an initial thickening and fibrosis of the lung interstitium, with upregulation of genes related to epithelial proliferation, tissue remodeling and hypoxia. At 28days, an evident increase in the deposition of collagen in the lungs was observed. This excessive deposition was accompanied by an upregulation of transcripts related to the extracellular matrix (TGFβ1, SNAI1 and SNAI2), indicating lung fibrosis. Administration of OCA protected against bleomycin-induced lung damage by suppressing molecular mechanisms related to epithelial-to-mesenchymal transition (EMT), inflammation and collagen deposition, with a dose-dependent reduction of proinflammatory cytokines such as IL-1β and IL-6, as well as TGF-β1 and SNAI1 expression. Pirfenidone, a recently approved treatment for idiopathic pulmonary fibrosis (IPF), significantly counteracted bleomycin-induced pro-fibrotic genes expression, but did not exert significant effects on IL-1β and IL-6. OCA treatment in bleomycin-challenged rats also improved pulmonary function, by effectively normalizing airway resistance to inflation and lung stiffness in vivo. Results with OCA were similar, or even superior, to those obtained with pirfenidone. In conclusion, our results suggest an important protective effect of OCA against bleomycin-induced lung fibrosis by blunting critical mediators in the pathogenesis of IPF.
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.affiliation: Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Drug Research and Child Care, University of Florence, Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Corcetto
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Corno
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maneschi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: Intercept Pharmaceuticals, New York, NY, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy; I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy; I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy. Electronic address: linda.vignozzi@unifi.it.
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001761:Bleomycin; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007249:Inflammation; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D020257:Ventricular Remodeling; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001761:Bleomycin; D002635:Chenodeoxycholic Acid; D003094:Collagen; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
keywords: Bleomycin; Epithelial-to-mesenchymal cell transition; Farnesoid X Receptor; Inflammation; Obeticholic acid; Pulmonary fibrosis