AJP - Lung Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol 277: L65-L78, 1999;
1040-0605/99 $5.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krymskaya, V. P.
Right arrow Articles by Panettieri, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krymskaya, V. P.
Right arrow Articles by Panettieri, R. A., Jr.
Vol. 277, Issue 1, L65-L78, July 1999

Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation

Vera P. Krymskaya1, Raymond B. Penn2, Michael J. Orsini2, Pamela H. Scott3, Robin J. Plevin3, Trevor R. Walker4, Andrew J. Eszterhas1, Yassine Amrani1, Edwin R. Chilvers4, and Reynold A. Panettieri Jr.1

1 Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia 19104-4283; 2 Department of Pharmacology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; 3 Department of Physiology and Pharmacology, Royal College, University of Strathclyde, Glasgow G1 1XW; and 4 Rayne Laboratory, Respiratory Medicine Unit, Department of Medicine (Royal Infirmary of Edinburgh), University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom

Hypertrophy and hyperplasia of airway smooth muscle (ASM) are important pathological features that contribute to airflow obstruction in chronic severe asthma. Despite considerable research effort, the cellular mechanisms that modulate ASM growth remain unknown. Recent evidence suggests that mitogen-induced activation of phosphoinositide (PI)-specific phospholipase C (PLC) and PI-dependent calcium mobilization are neither sufficient nor necessary to stimulate human ASM proliferation. In this study, we identify phosphatidylinositol (PtdIns) 3-kinase as a key regulator of human ASM proliferation. Pretreatment of human ASM with the PtdIns 3-kinase inhibitors wortmannin and LY-294002 significantly reduced thrombin- and epidermal growth factor (EGF)-induced DNA synthesis (IC50 ~10 nM and ~3 µM, respectively). In separate experiments, wortmannin and LY-294002 markedly inhibited PtdIns 3-kinase and 70-kDa S6 protein kinase (pp70S6k) activation induced by stimulation of human ASM cells with EGF and thrombin but had no effect on EGF- and thrombin-induced p42/p44 mitogen-activated protein kinase (MAPK) activation. The specificity of wortmannin and LY-294002 was further suggested by the demonstrated inability of these compounds to alter thrombin-induced calcium transients, total PI hydrolysis, or basal cAMP levels. Transient expression of constitutively active PtdIns 3-kinase (p110*) activated pp70S6k, whereas a dominant-negative PtdIns 3-kinase (Delta p85) blocked EGF- and thrombin-stimulated pp70S6k activity. Collectively, these data suggest that activation of PtdIns 3-kinase is required for the mitogenic effect of EGF and thrombin in human ASM cells. Further investigation of the role of PtdIns 3-kinase may offer new therapeutic approaches in the treatment of diseases characterized by smooth muscle cell hyperplasia such as asthma and chronic bronchitis.

asthma; thrombin; airway remodeling; epidermal growth factor; p42/p44 mitogen-activated protein kinase; 70-kDa S6 protein kinase


This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. S. Sacks, A. L. Firth, C. V. Remillard, N. Agange, J. Yau, E. A. Ko, and J. X.-J. Yuan
Thrombin-mediated increases in cytosolic [Ca2+] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells
Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L1048 - L1055.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
J. K. Bentley and M. B. Hershenson
Airway Smooth Muscle Growth in Asthma: Proliferation, Hypertrophy, and Migration
Proceedings of the ATS, January 1, 2008; 5(1): 89 - 96.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. Gillibert-Duplantier, V. Neaud, J.-F. Blanc, P. Bioulac-Sage, and J. Rosenbaum
Thrombin inhibits migration of human hepatic myofibroblasts
Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G128 - G136.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
S. Xie, M. B. Sukkar, R. Issa, N. M. Khorasani, and K. F. Chung
Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta
Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L245 - L253.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
N. Takeda, M. Kondo, S. Ito, Y. Ito, K. Shimokata, and H. Kume
Role of RhoA Inactivation in Reduced Cell Proliferation of Human Airway Smooth Muscle by Simvastatin
Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 722 - 729.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
E. A. Goncharova, D. A. Goncharov, M. Spaits, D. J. Noonan, E. Talovskaya, A. Eszterhas, and V. P. Krymskaya
Abnormal Growth of Smooth Muscle-Like Cells in Lymphangioleiomyomatosis: Role for Tumor Suppressor TSC2
Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 561 - 572.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. K. Brown, M. D. Hollenberg, and C. A. Jones
Tryptase activates phosphatidylinositol 3-kinases proteolytically independently from proteinase-activated receptor-2 in cultured dog airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L259 - L269.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. V. Remillard and J. X.-J. Yuan
PGE2 and PAR-1 in pulmonary fibrosis: a case of biting the hand that feeds you?
Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L789 - L792.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. V. Gerasimovskaya, D. A. Tucker, and K. R. Stenmark
Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation
J Appl Physiol, February 1, 2005; 98(2): 722 - 731.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
X. Su, E. M. Smolock, K. N. Marcel, and R. S. Moreland
Phosphatidylinositol 3-kinase modulates vascular smooth muscle contraction by calcium and myosin light chain phosphorylation-independent and -dependent pathways
Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H657 - H666.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. Amrani, O. Tliba, D. Choubey, C.-D. Huang, V. P. Krymskaya, A. Eszterhas, A. L. Lazaar, and R. A. Panettieri Jr.
IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway
Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L1063 - L1071.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
H. Wang, J. J. Ubl, R. Stricker, and G. Reiser
Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways
Am J Physiol Cell Physiol, November 1, 2002; 283(5): C1351 - C1364.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
K. Parameswaran, G. Cox, K. Radford, L. J. Janssen, R. Sehmi, and P. M. O'Byrne
Cysteinyl Leukotrienes Promote Human Airway Smooth Muscle Migration
Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 738 - 742.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
E. A. Goncharova, A. J. Ammit, C. Irani, R. G. Carroll, A. J. Eszterhas, R. A. Panettieri, and V. P. Krymskaya
PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L354 - L363.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
A. J. Ammit and R. A. Panettieri Jr.
Signal Transduction in Smooth Muscle: Invited Review: The circle of life: cell cycle regulation in airway smooth muscle
J Appl Physiol, September 1, 2001; 91(3): 1431 - 1437.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
C. Patterson, G. A. Stouffer, N. Madamanchi, and M. S. Runge
New Tricks for Old Dogs : Nonthrombotic Effects of Thrombin in Vessel Wall Biology
Circ. Res., May 25, 2001; 88(10): 987 - 997.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
V. P. Krymskaya, A. J. Ammit, R. K. Hoffman, A. J. Eszterhas, and R. A. Panettieri Jr.
Activation of class IA PI3K stimulates DNA synthesis in human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L1009 - L1018.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J.-H. Lee, P. R. A. Johnson, M. Roth, N. H. Hunt, and J. L. Black
ERK activation and mitogenesis in human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L1019 - L1029.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
K. Page, J. Li, Y. Wang, S. Kartha, R. G. Pestell, and M. B. Hershenson
Regulation of Cyclin D1 Expression and DNA Synthesis by Phosphatidylinositol 3-Kinase in Airway Smooth Muscle Cells
Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 436 - 443.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
V. P. Krymskaya, M. J. Orsini, A. J. Eszterhas, K. C. Brodbeck, J. L. Benovic, R. A. Panettieri Jr., and R. B. Penn
Mechanisms of Proliferation Synergy by Receptor Tyrosine Kinase and G Protein-Coupled Receptor Activation in Human Airway Smooth Muscle
Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 546 - 554.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
M. B. Hershenson and M. K. Abe
Mitogen-Activated Signaling in Airway Smooth Muscle . A Central Role for Ras
Am. J. Respir. Cell Mol. Biol., December 1, 1999; 21(6): 651 - 654.
[Full Text]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. Irani, E. A. Goncharova, D. S. Hunter, C. L. Walker, R. A. Panettieri, and V. P. Krymskaya
Phosphatidylinositol 3-kinase but not tuberin is required for PDGF-induced cell migration
Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L854 - L862.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. R. Simon, S. Takahashi, M. Severgnini, B. L. Fanburg, and B. H. Cochran
Role of the JAK-STAT pathway in PDGF-stimulated proliferation of human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1296 - L1304.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online