Global gene expression patterns in the post-pneumonectomy lung of adult mice.
BACKGROUND
Adult mice have a remarkable capacity to regenerate functional alveoli following either lung resection or injury that exceeds the regenerative capacity observed in larger adult mammals. The molecular basis for this unique capability in mice is largely unknown. We examined the transcriptomic responses to single lung pneumonectomy in adult mice in order to elucidate prospective molecular signaling mechanisms used in this species during lung regeneration.


METHODS
Unilateral left pneumonectomy or sham thoracotomy was performed under general anesthesia (n = 8 mice per group for each of the four time points). Total RNA was isolated from the remaining lung tissue at four time points post-surgery (6 hours, 1 day, 3 days, 7 days) and analyzed using microarray technology.


RESULTS
The observed transcriptomic patterns revealed mesenchymal cell signaling, including up-regulation of genes previously associated with activated fibroblasts (Tnfrsf12a, Tnc, Eln, Col3A1), as well as modulation of Igf1-mediated signaling. The data set also revealed early down-regulation of pro-inflammatory cytokine transcripts and up-regulation of genes involved in T cell development/function, but few similarities to transcriptomic patterns observed during embryonic or post-natal lung development. Immunohistochemical analysis suggests that early fibroblast but not myofibroblast proliferation is important during lung regeneration and may explain the preponderance of mesenchymal-associated genes that are over-expressed in this model. This again appears to differ from embryonic alveologenesis.


CONCLUSIONS
These data suggest that modulation of mesenchymal cell transcriptome patterns and proliferation of S100A4 positive mesenchymal cells, as well as modulation of pro-inflammatory transcriptome patterns, are important during post-pneumonectomy lung regeneration in adult mice.
Paxson
Julia A
JA
Department of Clinical Sciences, Lung Function Testing Laboratory, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA. julia.paxson@tufts.edu
Parkin
Christopher D
CD
Iyer
Lakshmanan K
LK
Mazan
Melissa R
MR
Ingenito
Edward P
EP
Hoffman
Andrew M
AM
D000199:Actins / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011013:Pneumonectomy; D012313:RNA / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013908:Thoracotomy; D013997:Time Factors
D000199:Actins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D012313:RNA