Role of Transforming Growth Factor-Alpha (TGF-α) in Neonatal Lung Disease
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Several clinical studies have associated increased EGF receptor signaling due to increased ligands such as TGF-α, with lung remodeling in BPD, cystic fibrosis and pulmonary fibrosis. In addition, several of the insults/stimuli, such as hyperoxia, that are thought to play a role in the etiology of BPD have been shown to induce expression of TGF-α and other EGF receptor ligands. To determine the role of elevated EGF receptor signaling in the lung, transgenic mice expressing TGF-α specifically in the lung were generated using the human surfactant protein-C (SP-C) promoter (SPC-TGF-α mice)(figure 1)(Korfhagen et al. 2004). We have shown that elevated expression of TGF-α disrupts vascular as well as alveolar morphogenesis (figure 2 shows lung histology & figure 3 shows arteriogram analysis), and causes severe vascular remodeling (figure 4) and pulmonary hypertension (Le Cras et al. 2003). Hence, this work showed that TGF-a disrupts both vascular and alveolar morphogenesis, leading to vascular remodeling and pulmonary hypertension, key pathologic features in BPD.
In infants who are exposed to injurious stimuli, such as hyperoxia or infection, cytokines and growth factors such as TGF-α may only be increased for brief or limited periods of time. To address the question of whether transient increases in TGF-α are sufficient to cause neonatal lung disease we utilized conditional TGF-α transgenic mice (CCSP-rtTA/tetO-TGF-α)(Hardie et al. 2004). The conditional TGF-a mice allowed us to target induction of TGF-α in a lung specific manner using doxycycline (Dox) to the postnatal phase of lung morphogenesis (figure 5 shows the breeding regime to generate the bitransgenic mice and figure 6 shows how the bitransgenic system works). Using this system we found that induction of TGF-α during the alveolar phase of postnatal lung development disrupted alveolar (figure 7) and vascular morphogenesis (figure 8), and caused pulmonary hypertension (Le Cras et al. 2004). These structural abnormalities persisted into adulthood, well after TGF-α levels had returned to baseline. Hence, our study showed that even transient increases in TGF-α in the neonatal lung can have severe and long-term consequences on lung structure and function into adulthood. This work was published along with an accompanying editorial, highlighting the importance of our work as it relates to the early origins of adult lung disease (Massaro & Massaro 2004).
References
Korfhagen TR, Swantz RJ, Wert SE, McCarty JM, Kerlakian CB, Glasser SW, and Whitsett JA. (1994) Respiratory epithelial cell expression of human transforming growth factor-α induces lung fibrosis in transgenic mice. J. Clin. Invest. 93(4):1691-1699
Le Cras, TD, WD Hardie, K Fagan, JA Whitsett, and TR Korfhagen. (2003) Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing Transforming growth factor-α. Am. J. Physiol. (Lung Cell Mol. Physiol.) 285 (5): L1046-L1054
WD Hardie, TD Le Cras, K Jiang, JW Tichelaar, M Azhar, and TR Korfhagen. (2004) Conditional expression of transforming growth factor-α in the adult mouse lung causes progressive pulmonary fibrosis. Am. J. Physiol. (Lung Cell Mol. Physiol.) 286: L741-L749
Le Cras, TD, WD Hardie, JA Whitsett, and TR Korfhagen. (2004) Transient induction of TGF-α a disrupts lung morphogenesis, causing pulmonary disease in adulthood. Am. J. Physiol. (Lung Cell Mol. Physiol.) 287:L718-L729
Massaro D, and G DeCarlo Massaro. (2004) Critical period for alveologenesis and early determinants of adult pulmonary disease. Am J Physiol Lung Cell Mol Physiol 287: L715-L717
Contact Information
Tim D. Le Cras PhD
Associate Professor of Pediatrics
Division of Pulmonary Biology
Cincinnati Children's Hospital Medical Center
3333 Burnet Ave., Cincinnati, Ohio 45229-3039
Phone: 513-636-8151
Fax: 513-636-7868
Email: tim.lecras@cchmc.org
