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Tissue remodeling gene expression in a murine model of chronic rhinosinusitis
Nathan B Sautter1, Katherine L Delaney, Frances A Hausman
1Oregon Health Sciences University, Department of Otolaryngology-Head and Neck Surgery, Portland, Oregon 97239, USA. sauttern@ohsu.edu
Objective/Hypothesis:
The matrix metalloproteinase (MMP), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) families regulate tissue remodeling in many normal and pathophysiologic processes. We hypothesize that induction of chronic sinonasal inflammation will be associated with changes in regulation of these tissue remodeling cytokines.
Methods:
Balb/c mice aged 8 to 12 weeks were sensitized and treated with intranasal Aspergillus fumigatis (AF) three times per week for 1 week, 3 weeks, 2 months, and 3 months (n = 8 each time point). Sinonasal tissues were evaluated for changes in MMP, FGF, and BMP regulation using standard RT-PCR techniques. Additional snouts were processed for histology and immunohistochemistry. Untreated mouse snouts of identical age were used as controls.
Results:
Significant upregulation of MMP8 was observed at 2 months, and MMP1a, MMP7, MMP8, and MMP12 were all significantly upregulated at 3 months. FGF3 was significantly upregulated at 3 weeks and 3 months, and FGF5, FGF6, and FGF8 were all significantly upregulated at 3 months. BMP8b and BMP9 were significantly upregulated at 3 months. Histologic analysis revealed mucosal, stromal, and mucin gland hypertrophy, increased mucin production, and metaplasia with loss of cilia. Antibody staining was strongly positive in the AF-treated group.
Conclusions:
Induction of CRS is associated with time-dependent changes in tissue remodeling cytokine expression occurring in conjuction with inflammatory tissue changes. Antibody staining for upregulated cytokines suggests local production within the sinonasal mucosa. Further study is required to better understand the association between BMP, FGF, and MMP regulation and tissue remodeling changes resulting from chronic inflammation.
Insights
Chronic sinonasal inflammation in mice led to increased expression of tissue remodeling cytokines like matrix metalloproteinases (MMPs), fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). These changes correlated with inflammatory tissue alterations, suggesting local cytokine production.
Area of Science:
- Molecular biology
- Immunology
- Otolaryngology
Background:
- Matrix metalloproteinases (MMPs), fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs) are key regulators of tissue remodeling.
- Chronic sinonasal inflammation is a complex condition involving significant tissue changes.
Purpose of the Study:
- To investigate the hypothesis that chronic sinonasal inflammation alters the regulation of MMP, FGF, and BMP cytokine families.
- To examine the temporal relationship between inflammation induction and changes in these specific cytokine expressions.
Main Methods:
- Balb/c mice were exposed to intranasal Aspergillus fumigatus (AF) over periods of 1 week to 3 months.
- Sinonasal tissues were analyzed for MMP, FGF, and BMP gene expression using RT-PCR.
- Histology and immunohistochemistry were employed to assess tissue morphology and cytokine localization.
Main Results:
- Significant upregulation of MMPs (MMP8, MMP1a, MMP7, MMP12) was observed at 2 and 3 months post-induction.
- FGFs (FGF3, FGF5, FGF6, FGF8) and BMPs (BMP8b, BMP9) also showed significant upregulation at 3 months.
- Histological analysis confirmed mucosal and glandular hypertrophy, increased mucin production, and metaplasia with cilia loss in AF-treated mice.
Conclusions:
- Chronic rhinosinusitis (CRS) induction is linked to time-dependent alterations in tissue remodeling cytokine expression.
- Antibody staining indicates local production of these upregulated cytokines within the sinonasal mucosa.
- Further research is needed to elucidate the precise role of BMP, FGF, and MMP regulation in chronic inflammation-induced tissue remodeling.
