Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta

Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L245-53. doi: 10.1152/ajplung.00068.2007. Epub 2007 Apr 27.


Airway smooth muscle (ASM) hyperplasia is a characteristic feature of the asthmatic airway, but the underlying mechanisms that induce ASM hyperplasia remain unknown. Because transforming growth factor (TGF)-beta is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic signaling pathways in ASM cells. We obtained ASM cells by laser capture microdissection of bronchial biopsies and found that ASM cells from asthmatic patients expressed TGF-beta1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-beta1 stimulated the growth of nonconfluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration-dependent manner. The mitogenic activity of TGF-beta1 on ASM cells was inhibited by selective inhibitors of TGF-beta receptor I kinase (SD-208), phosphatidylinositol 3-kinase (PI3K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NF-kappaB (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGF-beta1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector-expressing Smad4, Smad7, or dominant-negative Smad3 and found no involvement of these Smads in TGF-beta1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-beta1-induced proliferation. Our findings suggest that TGF-beta1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-kappaB is also involved in the TGF-beta1 mitogenic signaling, but Smad pathway does not appear important.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asthma / metabolism
  • Cell Proliferation / drug effects
  • Culture Media, Serum-Free
  • Dexamethasone / pharmacology
  • Down-Regulation / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Hyperplasia
  • Male
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology*
  • NF-kappa B / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Glucocorticoid / agonists
  • Receptors, Transforming Growth Factor beta
  • Respiratory System / drug effects
  • Respiratory System / pathology*
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology


  • Culture Media, Serum-Free
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta1
  • Dexamethasone
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • Receptor, Transforming Growth Factor-beta Type I