In vivo disruption of TGF-beta signaling by Smad7 in airway epithelium alleviates allergic asthma but aggravates lung carcinogenesis in mouse.

Abstract

BACKGROUND:

TGF-beta 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-beta in immune cells to the development of allergic asthma and how TGF-beta signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-beta 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-beta 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-beta 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-beta signaling specifically in airway epithelium during the development of allergic asthma and lung cancer.

• Authors: Xiaolin Luo, Qiurong Ding, Min Wang, Zhigang Li, Kairui Mao, Bing Sun, Yi Pan, Zhenzhen Wang, Ying Qin Zang, Yan Chen
• Journal: PloS one (PLoS One) Vol. 5 Issue 4 Pg. e10149 (Apr 13 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20405019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Smad7 Protein
• Smad7 protein, mouse
• Transforming Growth Factor beta
• Urethane
• Ovalbumin

Topics

• Animals
• Asthma (chemically induced, etiology, therapy)
• Cytokines (analysis)
• Disease Models, Animal
• Genetic Therapy
• Inflammation (prevention & control)
• Lung Neoplasms (chemically induced, etiology, therapy)
• Mice
• Mice, Transgenic
• Ovalbumin
• Respiratory Mucosa (metabolism)
• Signal Transduction (drug effects)
• Smad7 Protein (genetics, pharmacology)
• Th2 Cells
• Transforming Growth Factor beta (antagonists & inhibitors, physiology)
• Urethane