[HTML][HTML] In Vivo Disruption of TGF-β Signaling by Smad7 in Airway Epithelium Alleviates Allergic Asthma but Aggravates Lung Carcinogenesis in Mouse

X Luo, Q Ding, M Wang, Z Li, K Mao, B Sun, Y Pan… - PLoS …, 2010 - journals.plos.org
X Luo, Q Ding, M Wang, Z Li, K Mao, B Sun, Y Pan, Z Wang, YQ Zang, Y Chen
PLoS One, 2010journals.plos.org
Background TGF-β has been postulated to play an important role in the maintenance of
epithelial homeostasis and the development of epithelium-derived cancers. However, most
of previous studies are mainly focused on the function of TGF-β in immune cells to the
development of allergic asthma and how TGF-β signaling in airway epithelium itself in
allergic inflammation is largely unknown. Furthermore, the in vivo TGF-β function specifically
in the airway epithelium during lung cancer development has been largely elusive …
Background
TGF-β has been postulated to play an important role in the maintenance of epithelial homeostasis and the development of epithelium-derived cancers. However, most of previous studies are mainly focused on the function of TGF-β in immune cells to the development of allergic asthma and how TGF-β signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-β function specifically in the airway epithelium during lung cancer development has been largely elusive.
Methodology/Principal Findings
To evaluate the in vivo contribution of TGF-β signaling in lung epithelium to the development of allergic disease and lung cancer, we generated a transgenic mouse model with Smad7, an intracellular inhibitor of TGF-β signaling, constitutively expressed in mouse airway Clara cells using a mouse CC10 promoter. The mice were subjected to the development of OVA-induced allergic asthma and urethane-induced lung cancer. The Smad7 transgenic animals significantly protected from OVA-induced asthma, with reduced airway inflammation, airway mucus production, extracellular matrix deposition, and production of OVA-specific IgE. Further analysis of cytokine profiles in lung homogenates revealed that the Th2 cytokines including IL-4, IL-5 and IL-13, as well as other cytokines including IL-17, IL-1, IL-6, IP10, G-CSF, and GM-CSF were significantly reduced in the transgenic mice upon OVA induction. In contrast, the Smad7 transgenic animals had an increased incidence of lung carcinogenesis when subjected to urethane treatment.
Conclusion/Significance
These studies, therefore, demonstrate for the first time the in vivo function of TGF-β signaling specifically in airway epithelium during the development of allergic asthma and lung cancer.
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