Mechanisms of Induction of Airway Smooth Muscle Hyperplasia by Transforming Growth Factor-I?

Publisher:
American Physiological Society
Publication Type:
Journal article
Citation:
Khorasani, Nadia et al. 2007, 'Mechanisms of Induction of Airway Smooth Muscle Hyperplasia by Transforming Growth Factor-I?', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 293, no. 1, pp. L245-L253.
Issue Date:
2007
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Because transforming growth factor (TGF)-I? 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-I?1 mRNA and protein to a greater extent than non-asthmatic individuals using real-time RTPCR and immunohistochemistry, respectively. TGF-I?1 stimulated the growth of non-confluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration dependent manner. The mitogenic activity of TGF-I?1 on ASM cells was inhibited by selective inhibitors of TGF-I? receptor-I kinase (SD-208), of phosphatidylinositol 3-kinase (PI3K, LY294002), ERK (PD98059), JNK (SP600125) and NF-I?B (AS602868). On the other hand, p38 MAPK inhibitor (SB203580) augmented TGF-I?1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector expressing Smad 4, Smad 7 or negative dominant Smad3 and found no involvement of these Smads in TGF-I?1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-I?1-induced proliferation. Our findings suggest that TGF-I?1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK and JNK, while p38 MAPK is a negative regulator. NF-I?B is also involved in the TGF-I?1 mitogenic signaling but Smad pathway does not appear important.
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