Lung-specific loss of a3 laminin worsens bleomycin-induced pulmonary fibrosis

Luisa I. Morales-Nebreda, Micah R. Rogel, Jessica L. Eisenberg, Kevin J. Hamill, Saul Soberanes, Recep Nigdelioglu, Monica Chi, Takugo Cho, Kathryn A. Radigan, Karen M. Ridge, Alexander V. Misharin, Alex Woychek, Susan Hopkinson, Harris Perlman, Gokhan M. Mutlu, Annie Pardo, Moises Selman, Jonathan C R Jones, G. R. Scott Budinger*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the a3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the a3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant proteinCpromoter (SPC-Cre) with mice expressing floxed alleles encoding the a3 laminin gene (Lama3fl/fl). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-b was worse in mice deficient in a3 laminin in the lung. Taken together, our results suggest that the loss of a3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-b. Thus, we speculate that the loss of the normal basement membrane organization of a3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

Original languageEnglish (US)
Pages (from-to)503-512
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2015

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Keywords

  • Development
  • Laminin
  • Matrix
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Morales-Nebreda, L. I., Rogel, M. R., Eisenberg, J. L., Hamill, K. J., Soberanes, S., Nigdelioglu, R., Chi, M., Cho, T., Radigan, K. A., Ridge, K. M., Misharin, A. V., Woychek, A., Hopkinson, S., Perlman, H., Mutlu, G. M., Pardo, A., Selman, M., Jones, J. C. R., & Scott Budinger, G. R. (2015). Lung-specific loss of a3 laminin worsens bleomycin-induced pulmonary fibrosis. American journal of respiratory cell and molecular biology, 52(4), 503-512. https://doi.org/10.1165/rcmb.2014-0057OC