Transgenic modeling of transforming growth factor-beta(1): role of apoptosis in fibrosis and alveolar remodeling.

Abstract

Inflammation and tissue remodeling with pathologic fibrosis are common consequences of Th2 responses in the lung and other organs. Interleukin (IL)-13 and transforming growth factor-beta1 (TGF-beta(1)) are frequently coexpressed in these responses and are believed to play important roles in the pathogenesis of Th2-induced pathologies. To shed light on the mechanisms of these responses, overexpression transgenic approaches were used to selectively target each of these cytokines to the murine lung. IL-13 proved to be a potent stimulator of eosinophilic inflammation, mucus metaplasia, tissue fibrosis, and alveolar remodeling. CC chemokines, specific chemokine receptors (CCR2, CCR1), adenosine metabolism, vascular endothelial growth factor, and IL-11 contributed to the genesis of these responses. IL-13 also induced tissue fibrosis, at least in part, via its ability to induce and activate TGF-beta(1). In the TGF-beta(1) transgenic mouse, epithelial apoptosis preceded the onset of tissue fibrosis and alveolar remodeling. In addition, chemical (Z-VAD-fmk) and genetic (null mutations of early growth response gene 1) interventions blocked apoptosis and ameliorated TGF-beta(1)-induced fibrosis and alveolar restructuring. These studies define an IL-13-TGF-beta(1) pathway of tissue remodeling that regulates inflammation, mucus metaplasia, apoptosis, vascular responses, and fibrosis in the lung. They also highlight the intimate relationship between apoptosis and fibrosis induced by TGF-beta(1). By defining the complexities of this pathway, these studies highlight sites at which therapies can be directed to control these important responses.

• Authors: Chun Geun Lee, Hye-Ryun Kang, Robert J Homer, Geoffrey Chupp, Jack A Elias
• Journal: Proceedings of the American Thoracic Society (Proc Am Thorac Soc) Vol. 3 Issue 5 Pg. 418-23 (Jul 2006) ISSN: 1546-3222 [Print] United States
• PMID: 16799085 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• DNA

Topics

• Animals
• Apoptosis (physiology)
• DNA (genetics)
• Gene Expression
• Humans
• Pulmonary Alveoli (metabolism, pathology)
• Pulmonary Fibrosis (genetics, metabolism, pathology)
• Transforming Growth Factor beta (genetics)
• Transforming Growth Factor beta1