Chest
Volume 125, Issue 2, February 2004, Pages 754-765
Journal home page for Chest

Impact of Basic Research on Tomorrow's Medicine
The Role of Transforming Growth Factor β in Lung Development and Disease

https://doi.org/10.1378/chest.125.2.754Get rights and content

Transforming growth factor (TGF) β plays an important role in normal pulmonary morphogenesis and function and in the pathogenesis of lung disease. The effect of TGFβ is regulated via a selective pathway of TGFβ synthesis and signaling that involves activation of latent TGFβ, specific TGFβ receptors, and intracellular signaling via Smad molecules. All three isoforms of TGFβ are expressed at high levels during normal lung development, being particularly important for branching morphogenesis and epithelial cell differentiation with maturation of surfactant synthesis. Small amounts of TGFβ are still present in the adult lung, and TGFβ is involved in normal tissue repair following lung injury. However, in a variety of forms of pulmonary pathology, the expression of TGFβ is increased. These include chronic lung disease of prematurity as well as several forms of acute and chronic adult lung disease. While TGFβ1 appears to be the predominant isoform involved, elevated levels of all three isoforms have been demonstrated. The increase in TGFβ precedes abnormalities in lung function and detectable lung pathology, but correlates with the severity of the disease. TGFβ plays a key role in mediating fibrotic tissue remodeling by increasing the production and decreasing the degradation of connective tissue via several mechanisms.

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.

References (141)

  • JN Finkelstein et al.

    Early alterations in extracellular matrix and transforming growth factor β gene expression in mouse lung indicative of late radiation fibrosis

    Int J Radiat Oncol Biol Phys

    (1994)
  • Y Zhao et al.

    Expression of transforming growth factor-β type I and type II receptors is altered in rat lungs undergoing bleomycin-induced pulmonary fibrosis

    Exp Mol Pathol

    (2000)
  • G Shanker et al.

    Regulation of extracellular matrix proteins by transforming growth factor β1 in cultured pulmonary endothelial cells

    Cell Biol Int

    (1999)
  • G Krishna et al.

    PG490–88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis

    Am J Pathol

    (2001)
  • A Fine et al.

    The effect of transforming growth factor-β on cell proliferation and collagen formation by lung fibroblasts

    J Biol Chem

    (1987)
  • HL Moses et al.

    TGF-β stimulation and inhibition of cell proliferation: new mechanistic insights

    Cell

    (1990)
  • M Gharaee-Kermani et al.

    Costimulation of fibroblast collagen and transforming growth factor β1 gene expression by monocyte chemoattractant protein-1 via specific receptors

    J Biol Chem

    (1996)
  • JP Grande

    Role of transforming growth factor-β in tissue injury and repair

    Proc Soc Exp Biol Med

    (1997)
  • J Massagué et al.

    TGFβ signalling through the Smad pathway

    Trends Cell Biol

    (1997)
  • MB Sporn et al.

    Transforming growth factor-β: recent progress and new challenges

    J Cell Biol

    (1992)
  • AB Kulkarni et al.

    Transforming growth factor-β1 null mutation in mice causes excessive inflammatory response and early death

    Proc Natl Acad Sci U S A

    (1993)
  • LP Sanford et al.

    TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes

    Development

    (1997)
  • MM Shull et al.

    Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease

    Nature

    (1992)
  • N Khalil et al.

    Increased production and immunohistochemical localization of transforming growth factor-β in idiopathic lung fibrosis

    Am J Respir Cell Mol Biol

    (1991)
  • A Magnan et al.

    Balance between alveolar macrophage IL-6 and TGF-β in lung-transplant recipients

    Am J Respir Crit Care Med

    (1996)
  • H Peters et al.

    Transforming growth factor-β in human glomerular injury

    Curr Opin Nephrol Hypertens

    (1997)
  • RG Wells

    Fibrogenesis. V: TGF-β signaling pathways

    Am J Physiol Gastrointest Liver Physiol

    (2000)
  • D Fujii et al.

    Transforming growth factor β gene maps to human chromosome 19 long arm and to mouse chromosome 7

    Somat Cell Mol Genet

    (1986)
  • DE Barton et al.

    Chromosomal mapping of genes for transforming growth factors β 2 and β 3 in man and mouse: dispersion of TGF-β gene family

    Oncogen Res

    (1988)
  • MF Beers et al.

    TGF-β1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung

    Am J Physiol

    (1998)
  • E Piek et al.

    Specificity, diversity, and regulation of TGF-β superfamily signaling

    FASEB J

    (1999)
  • CH Heldin et al.

    TGF-β signalling from cell membrane to nucleus through SMAD proteins

    Nature

    (1998)
  • UI Heine et al.

    Colocalization of TGF-β 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis

    Development

    (1990)
  • P Schmid et al.

    Differential expression of TGF β1, β2, and β3 genes during mouse embryogenesis

    Development

    (1991)
  • T Masui et al.

    Type β transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells

    Proc Natl Acad Sci U S A

    (1986)
  • AAW Ten Have-Opbroek

    Lung development in the mouse embryo

    Exp Lung Res

    (1991)
  • R Serra et al.

    TGFβ1 inhibits branching morphogenesis and N-myc expression in lung bud organ cultures

    Development

    (1994)
  • V Kaartinen et al.

    Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interactions

    Nat Genet

    (1995)
  • MF Chen et al.

    Human pulmonary acinar aplasia: reduction of transforming growth factor-β ligands and receptors

    Pediatr Res

    (1999)
  • RK Coker et al.

    Diverse cellular TGF-β1 and TGF-β3 gene expression in normal human and murine lung

    Eur Respir J

    (1996)
  • RW Pelton et al.

    Expression of transforming growth factor-β1, -β2- and β3 mRNA and protein in the murine lung

    Am J Respir Cell Mol Biol

    (1991)
  • A Magnan et al.

    Transforming growth factor β in normal human lung: preferential location in bronchial epithelial cells

    Thorax

    (1994)
  • WI De Boer et al.

    Transforming growth factor β1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (1998)
  • J Jagirdar et al.

    Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases

    Environ Health Perspect

    (1997)
  • N Khalil et al.

    TGF-β 1, but not TGF-β 2 or TGF-β 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study

    Am J Respir Cell Mol Biol

    (1996)
  • A Elssner et al.

    Elevated levels of interleukin-8 and transforming growth factor-β in bronchioalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells

    Transplantation

    (2000)
  • S Ahuja et al.

    Effect of transforming growth factor-β on early and late activation events in human T cells

    J Immunol

    (1993)
  • JH Kehrl et al.

    Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes

    J Immunol

    (1986)
  • AH Rook et al.

    Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytosolic activity and blunting of interferon responsiveness

    J Immunol

    (1986)
  • LA Ortiz et al.

    Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice

    Exp Lung Res

    (1998)
  • Cited by (0)

    View full text