Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production.

Yuko Horio,Mitsuomi Hirashima,Yohei Migiyama,Hidenori Ichiyasu,Toshiro Niki,Kazuhiko Fujii,Naoki Saita,Toyohisa Iriki,Keisuke Kojima,Hirotsugu Kohrogi,Paul Proost

doi:10.1371/journal.pone.0180742

Yuko Horio, Mitsuomi Hirashima + Show 9 more

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https://doi.org/10.1371/journal.pone.0180742

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Journal: PloS one	Publication Date: Jul 12, 2017
Citations: 16	License type: CC BY 4.0

Affiliation: Kumamoto University, Kagawa University

Abstract

PurposeChronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and pulmonary emphysema. Persistent inflammation and remodeling of the lungs and airways result in reduced lung function and a lower quality of life. Galectin (Gal)-9 plays a crucial role as an immune modulator in various diseases. However, its role in the pathogenesis of pulmonary emphysema is unknown. This study investigates whether Gal-9 is involved in pulmonary inflammation and changes in emphysema in a porcine pancreatic elastase (PPE)-induced emphysema model.Materials and methodsGal-9 was administered to mice subcutaneously once daily from 1 day before PPE instillation to day 5. During the development of emphysema, lung tissue and bronchoalveolar lavage fluid (BALF) were collected. Histological and cytological findings, concentrations of chemokines and matrix metalloproteinases (MMPs) in the BALF, and the influence of Gal-9 treatment on neutrophils were analyzed.ResultsGal-9 suppressed the pathological changes of PPE-induced emphysema. The mean linear intercept (Lm) of Gal-9-treated emphysema mice was significantly lower than that of PBS-treated emphysema mice (66.1 ± 3.3 μm vs. 118.8 ± 14.8 μm, respectively; p < 0.01). Gal-9 decreased the number of neutrophils and levels of MMP-9, MMP-2 and tissue inhibitor of metalloproteinases (TIMP)-1 in the BALF. The number of neutrophils in the BALF correlated significantly with MMPs levels. Interestingly, Gal-9 pretreatment in vitro inhibited the chemotactic activity of neutrophils and MMP-9 production from neutrophils. Furthermore, in Gal-9-deficient mice, PPE-induced emphysema progressed significantly compared with that in wild–type (WT) mice (108.7 ± 6.58 μm vs. 77.19 ± 6.97 μm, respectively; p < 0.01).ConclusionsThese results suggest that Gal-9 protects PPE-induced inflammation and emphysema by inhibiting the infiltration of neutrophils and decreasing MMPs levels. Exogenous Gal-9 could be a potential therapeutic agent for COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the world [1], and its prevalence and mortality rates are steadily increasing
Gal-9 decreased the number of neutrophils and levels of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinases (MMPs)-2 and tissue inhibitor of metalloproteinases (TIMP)-1 in the bronchoalveolar lavage fluid (BALF)
GalPharma and issued in Japan (4792390), the USA (8,268,324 and 8,580,743), EPC (1736541), Canada (2,561,696), India (239130), Korea (101222281) and China (200580010446) as of May 22, 2017, but these do not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. These results suggest that Gal-9 protects porcine pancreatic elastase (PPE)-induced inflammation and emphysema by inhibiting the infiltration of neutrophils and decreasing MMPs levels

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the world [1], and its prevalence and mortality rates are steadily increasing. A major component of COPD, is defined as the abnormal enlargement of airspaces distal to the terminal bronchioles accompanied by the irreversible destruction of alveolar walls. COPD is associated with infiltrations of variable inflammatory cells including neutrophils, alveolar macrophages, and CD4+ and CD8+ lymphocytes [5,6,7,8,9]. The recruitment and activation of neutrophils in the lungs is associated with the pathogenesis of emphysema. Current experimental evidence shows that proteases including matrix metalloproteinase-9 (MMP-9) released from activated neutrophils and macrophages digested elastin and other structural proteins, damaging alveolar units [6, 11] [9]. A recent study demonstrated that plasma levels of MMPs are associated with disease severity and are useful as biomarkers in COPD patients [12]

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