Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Daniela Urich, Jessica L. Eisenberg, Kevin J. Hamill, Desire Takawira, Sergio E. Chiarella, Saul Soberanes, Angel Gonzalez, Frank Koentgen, Tomas Manghi, Susan B. Hopkinson, Alexander V. Misharin, Harris Perlman, Gokhan M. Mutlu, G. R.Scott Budinger*, Jonathan C.R. Jones

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Laminins are heterotrimeric glycoproteins of the extracellular matrix that are secreted by epithelial cells and which are crucial for the normal structure and function of the basement membrane. We have generated a mouse harboring a conditional knockout of α3 laminin (Lama3fl/fl), one of the main laminin subunits in the lung basement membrane. At 60 days after intratracheal treatment of adult Lama3fl/fl mice with an adenovirus encoding Cre recombinase (Ad-Cre), the protein abundance of α3 laminin in whole lung homogenates was more than 50% lower than that in control-treated mice, suggesting a relatively long half-life for the protein in the lung. Upon exposure to an injurious ventilation strategy (tidal volume of 35 ml per kg of body weight for 2 hours), the mice with a knockdown of the α3 laminin subunit had less severe injury, as shown by lung mechanics, histology, alveolar capillary permeability and survival when compared with Ad-Null-treated mice. Knockdown of the α3 laminin subunit resulted in evidence of lung inflammation. However, this did not account for their resistance to mechanical ventilation. Rather, the loss of α3 laminin was associated with a significant increase in the collagen content of the lungs. We conclude that the loss of α3 laminin in the alveolar epithelium results in an increase in lung collagen, which confers resistance to mechanical injury.

Original languageEnglish (US)
Pages (from-to)2927-2937
Number of pages11
JournalJournal of cell science
Volume124
Issue number17
DOIs
StatePublished - Sep 1 2011

Keywords

  • Basement membrane
  • Extracellular matrix
  • Laminin
  • Lung

ASJC Scopus subject areas

  • Cell Biology

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    Urich, D., Eisenberg, J. L., Hamill, K. J., Takawira, D., Chiarella, S. E., Soberanes, S., Gonzalez, A., Koentgen, F., Manghi, T., Hopkinson, S. B., Misharin, A. V., Perlman, H., Mutlu, G. M., Budinger, G. R. S., & Jones, J. C. R. (2011). Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury. Journal of cell science, 124(17), 2927-2937. https://doi.org/10.1242/jcs.080911