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Impact of Basic Research on Tomorrow's MedicineThe Role of Transforming Growth Factor β in Lung Development and Disease
Section snippets
Structural Characteristics of TGFβ and Mechanisms of TGFβ Signaling
TGFβ exists in three isoforms (β1, β2, and β3), which are structurally related, with a 60 to 80% sequence homology.1 The TGFβ1, TGFβ2, and TGFβ3 genes have been mapped to chromosomes 19q13.1-q13.3,121q41,13 and 14q23–24,13 respectively. While many biological activities are identical or differ just in the intensity of the effect produced,1 some nonoverlapping functions have been discovered.
The pathway of TGFβ signaling is summarized in Figure 1. The TGFβ genes are transcriptionally activated by
The Role of TGFβ in Lung Development
The expression of TGFβ during embryogenesis has been studied in detail in the mouse. All three TGFβ genes are expressed at high levels during normal murine lung morphogenesis. TGFβ1 is expressed as early as day 11 of gestation in the cytoplasm of the stromal and the epithelial cells of the primordial ducts that constitute the two major cell types of the developing lung. It appears to play a central role in lung branching and increases between day 14 and day 15 in the mouse, when differentiation
Expression of TGFβ in the Normal Lung
Small amounts of TGFβ messenger RNA and protein as well as the type I and II receptors are still present in the normal lung after the completion of lung development. In mice, Coker et al29 found TGFβ1 messenger RNA localized to bronchiolar epithelium, Clara cells, mesenchymal cells, vascular endothelium, and alveolar cells, including macrophages; in this study, TGFβ3 messenger RNA was similarly distributed but not detected in the endothelium. In contrast, Pelton et al30 reported messenger RNA
The Role of TGFβ in the Pathogenesis of Lung Disease
A common characteristic of many forms of lung disease is an inflammatory process with a phase of tissue injury followed by a phase of repair.935 Injury of lung tissue by chemical, bacteriologic, or immunologic noxious effects leads to an induction of TGFβ that limits some of the inflammatory reactions and plays a key role in mediating tissue remodeling and repair.3363738 If the reparative processes are exaggerated and not adequately localized, lung pathology with fibrosis will ensue. This is
Profibrotic Effects of TGFβ
Remodeling of lung tissue with deposition of connective tissue can be mediated by TGFβ via several effects (Fig 2).
Genetic Polymorphism for TGFβ
There is increasing evidence for a genetic predisposition to pulmonary disease associated with fibrosis due to increased synthesis of TGFβ. Pretransplantation levels of TGFβ were significantly higher in patients developing liver or lung fibrosis after autologous bone marrow transplantation than in those who did not.124
In the DNA sequence encoding the leader sequence of the TGFβ1 protein, two genetic polymorphisms have been identified, located at codon 10 (either leucine or proline) and codon 25
Potential Mechanisms for Influencing Pulmonary Tissue Remodeling Via Regulation of TGFβ
Each of the steps along the pathway of synthesis, activation, and signaling of TGFβ represents a potential mechanism for regulating the activity of TGFβ (Fig 1). While these mechanisms are primarily important for physiologic regulation of TGFβ activity, there is increasing interest in using them to block excessive TGFβ–mediated tissue response to fibrogenic stimuli.
A variety of substances have been shown to suppress the transcriptional up-regulation of TGFβ in animal studies in vitro128 and in
ACKNOWLEDGMENT
We thank Matthias Emmert for assistance with the Figures.
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