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Vol. 54, Issue 6, 1007-1015, December 1998
Rayne Laboratory, Respiratory Medicine Unit, Department of Medicine
(Royal Infirmary of Edinburgh), University of Edinburgh Medical School,
Edinburgh EH8 9AG, UK (T.R.W., S.M.M., M.F.L.),
Pulmonary and Critical
Care Division, Department of Medicine, University of Pennsylvania
Medical Center, Philadelphia, Pennsylvania 19104-4283 (R.A.P.), and
Division of Respiratory Medicine (Addenbrooke's and Papworth
Hospitals), Department of Medicine, University of Cambridge School of
Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
(E.R.C.)
Proliferation of airway smooth muscle results from persistent
inflammatory cytokine and growth factor stimulation and is a critical
component of airway luminal narrowing in chronic asthma. Using primary
cultures of bovine tracheal smooth muscle (BTSM) cells to examine the
signaling basis of cell proliferation, platelet-derived growth factor
(PDGF)-BB and thrombin (which act through distinct receptor types) were
found to induce DNA synthesis in BTSM cells. Mitogen-induced DNA
synthesis could be completely inhibited by LY294002, a selective
phosphoinositide 3-kinase (PtdIns 3-kinase) inhibitor. Exposure of BTSM
cells to PDGF-BB or thrombin resulted in rapid activation of PtdIns
3-kinase and accumulation of phosphoinositide-3,4,5-trisphosphate. Protein kinase B, a novel signaling protein kinase, was identified in
BTSM cells and was activated by PDGF-BB and thrombin in a PtdIns 3-kinase-dependent manner; this may underlie mitogen-stimulated activation of p70s6k. PD98059, a mitogen-activated
protein kinase kinase 1 inhibitor, also partially inhibited PDGF-BB-
and thrombin-stimulated DNA synthesis, indicating a modulatory role for
mitogen-activated protein kinase in proliferation. GF109203X, Ro
31-8220, calphostin C, and chelerythrine (selective protein kinase C
inhibitors) had no effect on PDGF-BB- or thrombin-stimulated DNA
synthesis, suggesting that, despite abolishment of mitogen-stimulated
protein kinase C activity, cell proliferation stimulated by PDGF-BB and
thrombin is protein kinase C-independent. These data demonstrate that
the PtdIns 3-kinase/protein kinase B pathway represents a key signaling route in airway smooth muscle proliferation, with the mitogen-activated protein kinase kinase 1/mitogen-activated protein kinase cascade providing a complementary signal required for the full mitogenic response.
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