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Open AccessArticle

Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis

1
National Institute for Health and Medical Research (INSERM) UMR_S 1016, Cochin Institute, 75014 Paris, France
2
Université Paris-Descartes, Sorbonne Paris Cité, 75014 Paris, France
3
Service de Physiologie-Explorations Fonctionnelles, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), 75014 Paris, France
4
INSERM UMR_S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
5
Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France
6
National Centre for Scientific Research (CNRS) UMR 8104, 75014 Paris, France
7
Apaxen, 6041 Gosselies, Belgique
8
Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire, DHU Thorax Innovation, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), 94270 Le Kremlin-Bicêtre, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(12), 4105; https://doi.org/10.3390/ijms19124105
Received: 14 August 2018 / Revised: 12 December 2018 / Accepted: 14 December 2018 / Published: 18 December 2018
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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. View Full-Text
Keywords: idiopathic pulmonary fibrosis associated with pulmonary hypertension (IPF-PH); pulmonary vascular remodeling; molecular target; macrophage migration inhibitory factor idiopathic pulmonary fibrosis associated with pulmonary hypertension (IPF-PH); pulmonary vascular remodeling; molecular target; macrophage migration inhibitory factor
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Günther, S.; Bordenave, J.; Hua-Huy, T.; Nicco, C.; Cumont, A.; Thuillet, R.; Tu, L.; Quatremarre, T.; Guilbert, T.; Jalce, G.; Batteux, F.; Humbert, M.; Savale, L.; Guignabert, C.; Dinh-Xuan, A.-T. Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis. Int. J. Mol. Sci. 2018, 19, 4105.

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