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c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice.

Publication ,  Journal Article
Lindsey, JY; Ganguly, K; Brass, DM; Li, Z; Potts, EN; Degan, S; Chen, H; Brockway, B; Abraham, SN; Berndt, A; Stripp, BR; Foster, WM ...
Published in: Am J Respir Crit Care Med
June 15, 2011

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.

Duke Scholars

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Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

June 15, 2011

Volume

183

Issue

12

Start / End Page

1644 / 1652

Location

United States

Related Subject Headings

  • Respiratory System
  • Pulmonary Alveoli
  • Proto-Oncogene Proteins c-kit
  • Polymorphism, Single Nucleotide
  • Mice, Mutant Strains
  • Mice, Inbred Strains
  • Mice
  • Lung Compliance
  • Lung
  • Genetic Predisposition to Disease
 

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Lindsey, J. Y., Ganguly, K., Brass, D. M., Li, Z., Potts, E. N., Degan, S., … Hollingsworth, J. W. (2011). c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med, 183(12), 1644–1652. https://doi.org/10.1164/rccm.201007-1157OC
Lindsey, James Y., Koustav Ganguly, David M. Brass, Zhuowei Li, Erin N. Potts, Simone Degan, Huaiyong Chen, et al. “c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice.Am J Respir Crit Care Med 183, no. 12 (June 15, 2011): 1644–52. https://doi.org/10.1164/rccm.201007-1157OC.
Lindsey JY, Ganguly K, Brass DM, Li Z, Potts EN, Degan S, et al. c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1644–52.
Lindsey, James Y., et al. “c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice.Am J Respir Crit Care Med, vol. 183, no. 12, June 2011, pp. 1644–52. Pubmed, doi:10.1164/rccm.201007-1157OC.
Lindsey JY, Ganguly K, Brass DM, Li Z, Potts EN, Degan S, Chen H, Brockway B, Abraham SN, Berndt A, Stripp BR, Foster WM, Leikauf GD, Schulz H, Hollingsworth JW. c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1644–1652.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

June 15, 2011

Volume

183

Issue

12

Start / End Page

1644 / 1652

Location

United States

Related Subject Headings

  • Respiratory System
  • Pulmonary Alveoli
  • Proto-Oncogene Proteins c-kit
  • Polymorphism, Single Nucleotide
  • Mice, Mutant Strains
  • Mice, Inbred Strains
  • Mice
  • Lung Compliance
  • Lung
  • Genetic Predisposition to Disease