Role of map kinase activation in bovine tracheal smooth muscle mitogenesis. Kelleher, Michael D., Mark K. Abe, Tsung-Shu Oliver Chao, Manu Jain, Jonathan M. Green, Julian Solway, Marsha R. Rosner, and Marc B. Hershenson. Ben May Institute and the Departments of Pediatrics, Medicine, and Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637-1470
APStracts 2:0017L, 1995.
Abnormal growth of airway smooth muscle may play an important role in the pathogenesis of human airway diseases. Little is known about the proliferative responses of cultured airway smooth muscle cells, nor of the precise pathways responsible for mitogenesis in these cells. We assessed DNA synthesis, cell proliferation and mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes following exposure to four potential mitogens: platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1) and 5-hydroxytryptamine (5-HT). Stimulation with either PDGF or IGF-1 induced substantial increases in DNA synthesis and cell number, as reflected by [3H]-thymidine incorporation, flow cytometry, and methylene blue staining. Treatment with EGF or 5-HT, on the other hand, induced only modest DNA synthesis and no increase in cell number. Immunoblots and kinase renaturation assays of cell extracts demonstrated activation of both the 42 kD and 44 kD MAP kinases within minutes of either PDGF, IGF-1, EGF or 5-HT exposure. However, relative to EGF and 5-HT stimulation, late-phase MAP kinase activation was significantly greater following treatment with the mitogens PDGF and IGF-1. We conclude that in cultured bovine tracheal myocytes: (i) PDGF and IGF-1 are potent mitogens; (ii) MAP kinase may be activated subsequent to stimulation of either receptor tyrosine kinases (PDGF, EGF, IGF-1) or G protein-linked receptors lacking in known tyrosine kinase activity (5-HT): and (iii) unsustained MAP kinase activation is insufficient for mitogenesis. Finally, the finding that mitogenicity correlates with the late-phase of MAP kinase activation is consistent with the notion that sustained MAP kinase activation is important for bovine tracheal myocyte proliferation. 

Received 9 June 1994; accepted in final form 10 January 1995.
APS Manuscript Number L168-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.