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Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice
Yasuko Aida1, Yoko Shibata1, Shuichi Abe1
1Department of Cardiology, Pulmonology, and Nephrology, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Abstract:
Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.
Insights
MafB transcription factor suppression in alveolar macrophages reduced pulmonary emphysema development in mice. This suggests MafB influences macrophage maturation and matrix metalloproteinase expression, key factors in chronic obstructive pulmonary disease.
Area of Science:
- Pulmonary Medicine
- Immunology
- Molecular Biology
Background:
- Alveolar macrophages (AMs) are implicated in chronic obstructive pulmonary disease (COPD) pathogenesis.
- MafB transcription factor is upregulated in AMs following cigarette smoke exposure.
- The specific role of MafB in pulmonary emphysema remains unclear.
Purpose of the Study:
- To investigate the role of MafB in the development of pulmonary emphysema.
- To determine if suppressing MafB activity in macrophages affects emphysema progression.
Main Methods:
- Utilized wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice.
- Administered porcine pancreatic elastase to induce emphysema.
- Analyzed lung histology (mean linear intercept), bronchoalveolar lavage (BAL) cell populations, and macrophage surface markers (F4/80, CD11b) via flow cytometry.
- Assessed matrix metalloproteinase (MMP)-9 and MMP-12 expression using immunohistochemistry.
Main Results:
- Airspace enlargement was significantly reduced in elastase-treated DN-MafB Tg mice compared to WT mice.
- A decrease in AMs with projected pseudopods and mature AM subsets (F4/80+, CD11b+) was observed in DN-MafB Tg mice.
- MMP-9 and MMP-12 expression was significantly downregulated in BAL cells of DN-MafB Tg mice.
Conclusions:
- MafB appears to play a role in pulmonary emphysema development.
- Suppression of MafB may ameliorate emphysema by altering macrophage maturation and reducing MMP expression.
- Targeting MafB could be a potential therapeutic strategy for COPD.
