Overexpression of chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic mice, smokers and COPD.

Yuki Sakazaki,Toshio Ota,Seiya Kato,Ichiro Miki,Yuzuru Abe,Satoko Takei,Kiminori Fujimoto,Tomotaka Kawayama,Kazuko Matsunaga,Haruki Imaoka,Masanori Sawada,Hisamichi Aizawa,Tomoaki Hoshino,Hanako Oda,Shin-Ichi Takenaka,Dominik Hartl

doi:10.1371/journal.pone.0024177

Yuki Sakazaki, Toshio Ota + Show 14 more

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https://doi.org/10.1371/journal.pone.0024177

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Abstract

We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of −950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV1. Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients.

Highlights

Chronic obstructive pulmonary disease (COPD) is an important pulmonary inflammatory disease whose prevalence and associated mortality rates have been increasing [1,2]
We found that the levels of mRNAs for chitinase-like proteins chitinase 3-like 1 (Chi3l1), chitinase 3-like 3 (Chi3l3), and acidic mammalian chitinase (AMCase) were significantly increased in the lungs of IL-18-transgenic mice as compared with control wild-type mice
In group 1 (Table S1), we demonstrate that several genes including those for IL-18, chloride channel calcium activated 3 (Clca3), and the chitinase-related genes chitinase 3-like 3 (Chi3l3), Chi3like 1 (Chi3l1) and acidic mammalian chitinase (AMCase), were strongly upregulated in the lungs of Tg mice from 5 to 13 weeks of age

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is an important pulmonary inflammatory disease whose prevalence and associated mortality rates have been increasing [1,2]. In this disease, T cells (predominantly IFN-c-producing CD8+ T cells (type 1 cytotoxic T cells) and Th1 cells), neutrophils and macrophages are activated in the lungs [3,4], producing proteases such as neutrophil elastase and matrix metalloproteinase (MMP)-9, resulting in alveolar wall destruction (emphysematous change) and mucus hypersecretion. A significant negative correlation between the serum IL-18 level and %FEV1 has been reported in COPD [18] Taken together, these results provide strong support for the involvement of IL-18 in the pathogenesis of COPD

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