1. Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis
- Author
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Raphaël Thuillet, Timothée Quatremarre, Marc Humbert, Laurent Savale, Sven Günther, Carole Nicco, Thong Hua-Huy, Christophe Guignabert, Frédéric Batteux, Gaël Jalce, Anh Tuan Dinh-Xuan, Jennifer Bordenave, Amélie Cumont, Thomas Guilbert, Ly Tu, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC), Service de physiologie et explorations fonctionelles [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Université Paris-Saclay, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), APAXEN [Gosselies, Belgique], Service d'Anesthésie et de Soins Intensifs [Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This research was supported by grants from the French National Institute for Health and Medical Research (INSERM), the University of Paris-Sud and the University Paris-Saclay, the Marie Lannelongue Hospital, the French National Agency for Research (ANR) grant No. ANR-16-CE17-0014 (TAMIRAH), the Fondation de la Recherche Médicale (FRM) grant No. DEQ20150331712 (Equipe FRM 2015), the Legs Poix (Chancellerie des Universités de Paris), and in part by the Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), the Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, the LabEx LERMIT (grant No ANR-10-LABX-0033), and the French PAH patient association (HTAP France). S.G. is supported by the French Fonds de Dotation 'Recherche en Santé Respiratoire' (FRSR), Fondation du Souffle (FdS). J.B. is supported by the FRM., ANR-16-CE17-0014,TAMIRAH,Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement(2016), ANR-10-LABX-0033,LERMIT,Research Laboratory on Drugs and Therapeutic Innovation(2010), Guignabert, Christophe, Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement - - TAMIRAH2016 - ANR-16-CE17-0014 - AAPG2016 - VALID, Research Laboratory on Drugs and Therapeutic Innovation - - LERMIT2010 - ANR-10-LABX-0033 - LABX - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Pharmacology ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,CXCR4 ,molecular target ,lcsh:Chemistry ,Mice ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,Fibrosis ,Pulmonary fibrosis ,Medicine ,Lung ,lcsh:QH301-705.5 ,Spectroscopy ,General Medicine ,respiratory system ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,Computer Science Applications ,Intramolecular Oxidoreductases ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Female ,Receptors, CXCR4 ,Hypertension, Pulmonary ,idiopathic pulmonary fibrosis associated with pulmonary hypertension (IPF-PH) ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Vascular Remodeling ,Bleomycin ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Animals ,Humans ,Physical and Theoretical Chemistry ,Macrophage Migration-Inhibitory Factors ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Molecular Biology ,Inflammation ,business.industry ,Organic Chemistry ,Histocompatibility Antigens Class II ,Isoxazoles ,medicine.disease ,Pulmonary hypertension ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,Antigens, Differentiation, B-Lymphocyte ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,macrophage migration inhibitory factor ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Macrophage migration inhibitory factor ,business ,pulmonary vascular remodeling - Abstract
Background: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. Objectives: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. Methods: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. Results: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. Conclusions: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.
- Published
- 2018