Evidence for in vivo nicotine-induced alveolar interstitial fibroblast-to-myofibroblast transdifferentiation.
Nicotine exposure alters normal homeostatic pulmonary epithelial-mesenchymal paracrine signaling pathways, resulting in alveolar interstitial fibroblast (AIF)-to-myofibroblast (MYF) transdifferentiation. Though this has been described under in vitro conditions, it is not known if the same phenomenon also takes place in vivo. A well-established rodent model of lung damage following perinatal nicotine exposure was used. By probing for the well-established markers of fibroblast differentiation (parathyroid hormone-related protein [PTHrP], peroxisome proliferator-activated receptor gamma [PPARgamma], adipocyte differentiation-related protein, alpha-smooth muscle actin, and fibronectin) at the mRNA, protein, and tissue levels, the authors provide the first in vivo evidence for nicotine-induced AIF-to-MYF transdifferentiation. In addition, these data also provide the first evidence for nicotine-induced up-regulation of Wnt signaling, accompanying the down-regulation of PTHrP/PPARgamma signaling in vivo following nicotine exposure during pregnancy. These data provide an integrated mechanism for in utero nicotine-induced lung damage and how it could permanently alter the "developmental program" of the developing lung by disrupting critically important epithelial-mesenchymal interactions. More importantly, these data are likely to provide specific interventions to augment the pulmonary mesenchymal lipogenic pathway to ameliorate nicotine-induced in utero lung injury.
Krebs
Melissa
M
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Sakurai
Reiko
R
Torday
John S
JS
Rehan
Virender K
VK
D000199:Actins / Q000032:analysis; D000818:Animals; D054338:Cell Transdifferentiation; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D005353:Fibronectins / Q000032:analysis; D008168:Lung / Q000166:cytology / Q000187:drug effects; D055370:Lung Injury / Q000139:chemically induced* / Q000473:pathology; D008565:Membrane Proteins; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects*; D009538:Nicotine / Q000633:toxicity*; D047495:PPAR gamma / Q000032:analysis; D044162:Parathyroid Hormone-Related Protein / Q000032:analysis; D010455:Peptides / Q000032:analysis; D000070780:Perilipin-2; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012907:Smoking; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000032:analysis
D000199:Actins; D005353:Fibronectins; D008565:Membrane Proteins; D009538:Nicotine; D047495:PPAR gamma; D044162:Parathyroid Hormone-Related Protein; D010455:Peptides; D000070780:Perilipin-2; D012333:RNA, Messenger; D051153:Wnt Proteins; C498862:Acta2 protein, rat