TY - JOUR
T1 - Lung-specific loss of a3 laminin worsens bleomycin-induced pulmonary fibrosis
AU - Morales-Nebreda, Luisa I.
AU - Rogel, Micah R.
AU - Eisenberg, Jessica L.
AU - Hamill, Kevin J.
AU - Soberanes, Saul
AU - Nigdelioglu, Recep
AU - Chi, Monica
AU - Cho, Takugo
AU - Radigan, Kathryn A.
AU - Ridge, Karen M.
AU - Misharin, Alexander V.
AU - Woychek, Alex
AU - Hopkinson, Susan
AU - Perlman, Harris
AU - Mutlu, Gokhan M.
AU - Pardo, Annie
AU - Selman, Moises
AU - Jones, Jonathan C R
AU - Scott Budinger, G. R.
N1 - Publisher Copyright:
© 2015 by the American Thoracic Society.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
KW - Development
KW - Laminin
KW - Matrix
KW - Pulmonary fibrosis
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U2 - 10.1165/rcmb.2014-0057OC
DO - 10.1165/rcmb.2014-0057OC
M3 - Article
C2 - 25188360
AN - SCOPUS:84929657150
VL - 52
SP - 503
EP - 512
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 4
ER -