P Comeglio1, S Filippi2, E Sarchielli3, A Morelli3, I Cellai1, C Corno1, A Pini3, L Adorini4, G B Vannelli3, M Maggi1,5, L Vignozzi6,7. 1. Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Viale Pieraccini, 6, 50139, Florence, Italy. 2. Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of NEUROFARBA, University of Florence, Florence, Italy. 3. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 4. Intercept Pharmaceuticals, New York, NY, USA. 5. I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy. 6. Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Viale Pieraccini, 6, 50139, Florence, Italy. linda.vignozzi@unifi.it. 7. I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy. linda.vignozzi@unifi.it.
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.
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.
Authors: William G Carlos; Mary E Strek; Tisha S Wang; Harin Patel; Ganesh Raghu; Kevin C Wilson; Carey C Thomson Journal: Ann Am Thorac Soc Date: 2016-01
Authors: Dmitri V Pechkovsky; Antje Prasse; Florian Kollert; Kathrin M Y Engel; Jan Dentler; Werner Luttmann; Karlheinz Friedrich; Joachim Müller-Quernheim; Gernot Zissel Journal: Clin Immunol Date: 2010-07-31 Impact factor: 3.969
Authors: Linda Vignozzi; Annamaria Morelli; Sandra Filippi; Paolo Comeglio; Aravinda K Chavalmane; Matilde Marchetta; Mariateresa Toce; Ravit Yehiely-Cohen; Gabriella B Vannelli; Luciano Adorini; Mario Maggi Journal: J Sex Med Date: 2010-10-18 Impact factor: 3.802
Authors: Xiaoxin X Wang; Tao Jiang; Yan Shen; Yupanqui Caldas; Shinobu Miyazaki-Anzai; Hannah Santamaria; Cydney Urbanek; Nathaniel Solis; Pnina Scherzer; Linda Lewis; Frank J Gonzalez; Luciano Adorini; Mark Pruzanski; Jeffrey B Kopp; Jill W Verlander; Moshe Levi Journal: Diabetes Date: 2010-08-10 Impact factor: 9.461
Authors: Antoni Xaubet; Alejandra Marin-Arguedas; Sergio Lario; Julio Ancochea; Ferran Morell; Juan Ruiz-Manzano; Eulogio Rodriguez-Becerra; Jose M Rodriguez-Arias; Pablo Inigo; Sergi Sanz; Josep M Campistol; Joaquim Mullol; Cesar Picado Journal: Am J Respir Crit Care Med Date: 2003-05-13 Impact factor: 21.405