Abstract
Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that historically led to death within 3–5 years of diagnosis [1], antifibrotic medications, such as nintedanib, can significantly extend life expectancy [2,3]
Noting that Matrix metalloproteinase 7 (MMP7)− /− mice are protected from bleomycin-induced fibrosis [16] and that their airway epithelia are carpeted with cilia after injury [28] we focus on the roles of MMP7 and ciliogenesis in the Atp8b1 mouse model
Abnormal morphology of ciliated cells and club cells in the Atp8b1 mutant mouse and microarray data indicating decreased expression of ciliogenesis genes support a role for ciliogenesis in lung fibrosis in this mouse model
Summary
Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that historically led to death within 3–5 years of diagnosis [1], antifibrotic medications, such as nintedanib, can significantly extend life expectancy [2,3]. MMP7 distinguishes IPF from other types of interstitial lung disease with a sensitivity of 71.7% (range, 71–72.3%), specificity of 64.4% (63–66.3%), and diagnostic odds ratio of 4.7 (4.2–5.1) [5]. Despite these favorable test characteristics, guidelines published in 2018 from the American Thoracic Society do not support measuring serum MMP7 to diagnose IPF because of concern about false negatives, which could limit patient access to life-prolonging therapies [5]. Plasma MMP7 concentrations are significantly higher in IPF patients than in healthy controls,
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
