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

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)-β is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2007-07, Vol.293 (1), p.L245
Main Authors: Xie, Shaoping, Sukkar, Maria B, Issa, Razao, Khorasani, Nadia M, Kian Fan Chung
Format: Article
Language:English
Subjects:
Airway management
Asthma
Cells
Gene expression
Lungs
Proteins
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Summary: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)-β 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-β1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-β1 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 TGFβ1 on ASM cells was inhibited by selective inhibitors of TGF-β receptor I kinase (SD-208), phosphatidylinositol 3-kinase (P13K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NP-...B (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGFβ1-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-1β-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-β1-induced proliferation. Our findings suggest that TGF-β1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including P13 K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-...B is also involved in the TGF-β1 mitogenic signaling, but Smad pathway does not appear important. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.)
ISSN:1040-0605
1522-1504