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Original Research |

p53 signaling pathway polymorphisms associated with emphysematous changes in COPD patients

Shiro Mizuno, MD, PhD; Takeshi Ishizaki, MD, PhD; Maiko Kadowaki, MD, PhD; Masaya Akai, MD, PhD; Kohei Shiozaki, MD, PhD; Masaharu Iguchi, MD, PhD; Taku Oikawa, MD, PhD; Ken Nakagawa, MD, PhD; Kazuhiro Osanai, MD, PhD; Hirohisa Toga, MD, PhD; Jose Gomez-Arroyo, MD, PhD; Donatas Kraskauskas, DVM; Carlyne D. Cool, MD; Herman J. Bogaard, MD, PhD; Norbert F. Voelkel, MD
Author and Funding Information

COI disclosure: The authors declare that there are no competing interests to disclose.

Funding: These investigations have been supported by Grants-in-Aid for Scientific Research (No. 24591144) of Japan, and funds from the Victoria Johnson Center for Lung Research of the Virginia Commonwealth University.

1Division of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan

2Department of Respiratory Medicine, University of Fukui, Fukui, Japan

3Department of Respiratory Medicine, Fukui Red Cross Hospital, Fukui, Japan

4Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA, USA

5Department of Pathology, University of Colorado Health Science Center, LTRC repository, Aurora, Colorado

6VU University Medical Center, Amsterdam, the Netherlands

Correspondence to: Shiro Mizuno, MD, PhD, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.


Copyright 2017, . All Rights Reserved.


Chest. 2017. doi:10.1016/j.chest.2017.03.012
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Abstract

Background  The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) SNP309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema.

Methods  365 patients with a smoking history were included in this study, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by computed tomography scanning. SNPs, MDM2 mRNA and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and effect on cell proliferation and MDM2 promoter activity were measured.

Results  The polymorphisms of p53 and MDM2 genes were associated with emphysematous changes in the lung, and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLFs proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE.

Conclusions  Our data demonstrate that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in the lungs from smokers.


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