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Updated: Jun 3, 2026
Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice
Published on: January 16, 2015
c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice
James Y Lindsey1, Koustav Ganguly, David M Brass
1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Rationale:
Previously, we demonstrated a candidate region for susceptibility to airspace enlargement on mouse chromosome 5. However, the specific candidate genes within this region accounting for emphysema-like changes remain unrecognized. c-Kit is a receptor tyrosine kinase within this candidate gene region that has previously been recognized to contribute to the survival, proliferation, and differentiation of hematopoietic stem cells. Increases in the percentage of cells expressing c-Kit have previously been associated with protection against injury-induced emphysema.
Objectives:
Determine whether genetic variants of c-Kit are associated with spontaneous airspace enlargement.
Methods:
Perform single-nucleotide polymorphism association studies in the mouse strains at the extremes of airspace enlargement phenotype for variants in c-Kit tyrosine kinase. Characterize mice bearing functional variants of c-Kit compared with wild-type controls for the development of spontaneous airspace enlargement. Epithelial cell proliferation was measured in culture.
Measurements And Main Results:
Upstream regulatory single-nucleotide polymorphisms in the divergent mouse strains were associated with the lung compliance difference observed between the extreme strains. c-Kit mutant mice (Kit(W-sh)/(W-sh)), when compared with genetic controls, developed altered lung histology, increased total lung capacity, increased residual volume, and increased lung compliance that persist into adulthood. c-Kit inhibition with imatinib attenuated in vitro proliferation of cells expressing epithelial cell adhesion molecule.
Conclusions:
Our findings indicate that c-Kit sustains and/or maintains normal alveolar architecture in the lungs of mice. In vitro data suggest that c-Kit can regulate epithelial cell clonal expansion. The precise mechanisms that c-Kit contributes to the development of airspace enlargement and increased lung compliance remain unclear and warrants further investigation.
Insights
Genetic variants in the c-Kit gene are linked to spontaneous airspace enlargement in mice. This receptor tyrosine kinase plays a role in maintaining normal lung alveolar architecture and epithelial cell proliferation.
Area of Science:
- Pulmonary Medicine
- Genetics
- Cell Biology
Background:
- Susceptibility to airspace enlargement, a hallmark of emphysema, has been linked to a region on mouse chromosome 5.
- The specific genes responsible for emphysema-like changes within this region were previously unknown.
- c-Kit, a receptor tyrosine kinase, is crucial for hematopoietic stem cell function and has been associated with protection against injury-induced emphysema.
Purpose of the Study:
- To investigate the association between genetic variants of the c-Kit gene and spontaneous airspace enlargement.
- To determine if c-Kit plays a role in the development of emphysema-like lung changes.
Main Methods:
- Single-nucleotide polymorphism (SNP) association studies were conducted on mouse strains with extreme airspace enlargement phenotypes, focusing on c-Kit tyrosine kinase variants.
- Mice with functional c-Kit variants were compared to wild-type controls to assess spontaneous airspace enlargement.
- Epithelial cell proliferation was quantified in vitro.
Main Results:
- Upstream regulatory SNPs in c-Kit were associated with lung compliance differences between divergent mouse strains.
- c-Kit mutant mice exhibited altered lung histology, increased lung volumes (total lung capacity and residual volume), and persistent increases in lung compliance into adulthood.
- In vitro inhibition of c-Kit reduced the proliferation of cells expressing epithelial cell adhesion molecule.
Conclusions:
- c-Kit is essential for maintaining normal alveolar architecture in mouse lungs.
- In vitro findings suggest c-Kit regulates epithelial cell clonal expansion.
- Further research is needed to elucidate the precise mechanisms by which c-Kit influences airspace enlargement and lung compliance.
