Bleomycin-Induced Pulmonary Fibrosis in Transgenic Mice Carrying the Human <i>MUC5B</i> rs35705950 Variant
Suphachai Tharavecharak,
Hajime Fujimoto,
Taro Yasuma,
Corina N. D’Alessandro-Gabazza,
Masaaki Toda,
Atsushi Tomaru,
Haruko Saiki,
Mei Uemura,
Yurie Kogue,
Toshiyuki Ito,
Kazuki Furuhashi,
Tomohito Okano,
Atsuro Takeshita,
Kota Nishihama,
Ryoichi Ono,
Osamu Hataji,
Tetsuya Nosaka,
Tetsu Kobayashi,
Esteban C. Gabazza
Affiliations
Suphachai Tharavecharak
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Hajime Fujimoto
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Taro Yasuma
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Corina N. D’Alessandro-Gabazza
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Masaaki Toda
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Atsushi Tomaru
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Haruko Saiki
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Mei Uemura
Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Yurie Kogue
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Toshiyuki Ito
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Kazuki Furuhashi
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Tomohito Okano
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Atsuro Takeshita
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Kota Nishihama
Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Ryoichi Ono
Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan
Osamu Hataji
Respiratory Center, Matsusaka Municipal Hospital, Tonomachi1550, Matsusaka 515-8544, Mie, Japan
Tetsuya Nosaka
Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan
Tetsu Kobayashi
Department Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Esteban C. Gabazza
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan
Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal lung disease characterized by tissue scarring and declining lung function. The MUC5B promoter polymorphism rs35705950, a significant genetic predisposition for IPF, paradoxically associates with better survival and slower disease progression than other IPF genotypes. This study investigates the potential paradoxical protective effects of this MUC5B variant in lung fibrosis. For this purpose, we developed a transgenic mouse model overexpressing the human MUC5B rs35705950 variant in the proximal large airways. Lung fibrosis was induced through subcutaneous injection of bleomycin. Results demonstrated significantly reduced lung fibrosis severity in transgenic mice compared to wild-type mice, assessed by trichrome staining, Ashcroft scoring, and hydroxyproline levels. Additionally, transgenic mice showed significantly lower levels of inflammatory cells and cytokines (TNFα, IL-6, IFNγ) and growth factors (PDGF, CTGF, IL-13) in the bronchoalveolar lavage fluid and lung tissues. There was also a significant decrease in mRNA expressions of fibrosis-related markers (periostin, fibronectin, Col1a1). In summary, this study reveals that mucin overexpression related to the MUC5B rs35705950 variant in the large airways significantly attenuates lung fibrosis and inflammatory responses in transgenic mice. These findings suggest that the rs35705950 variant modulates inflammatory and fibrotic responses in the proximal airways, which may contribute to the slower disease progression observed in IPF patients carrying this variant. Our study offers a possible explanation for the paradoxical beneficial effects of the MUC5B variant despite its role as a significant predisposing factor for IPF.
