Proliferative aspects of airway smooth muscle

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Presentation transcript:

Proliferative aspects of airway smooth muscle Stuart J Hirst, PhD, James G Martin, MD, John V Bonacci, PhD, Vivien Chan, MB, BCh, Elizabeth D Fixman, PhD, Qutayba A Hamid, MD, PhD, Berenice Herszberg, DVM, Jean-Pierre Lavoie, DVM, Clare G McVicker, PhD, Lyn M Moir, PhD, Trang T.-B Nguyen, BSc, Qi Peng, PhD, David Ramos-Barbón, MD, Alastair G Stewart, PhD Journal of Allergy and Clinical Immunology Volume 114, Issue 2, Pages S2-S17 (August 2004) DOI: 10.1016/j.jaci.2004.04.039

Fig 1 Key signal transduction mechanisms that operate in ASM to regulate cell cycle entry and DNA synthesis. Mitogens acting predominantly through RTK (eg, PDGF) or GPCR (eg, thrombin) activate small GTPase p21ras proteins, which interact with various downstream effectors. These include Raf-1 and PI3K. Raf-1 activates MEK1, which then phosphorylates ERK. PI3K, via 3-phosphorylated phosphoinositides such as 3,4,5-trisphosphate (PIP3), recruits phosphoinositide-dependent kinase 1 (PDK1), which in turn leads to maximal protein kinase B (Akt) activation and downstream activation of p70S6K and members of the Rho family GTPases, Rac1 and Cdc42. These form part of the NADPH oxidase complex that generates ROSs such as H2O2, which may lead to cyclin D1 activation via nuclear factor-κB (NF-κB) or JAK2. Thus, the ERK and PI3K pathways are considered to be 2 major, independent signaling pathways regulating ASM cell proliferation. PIP2, Phosphoinositide 3,4-bisphosphate. SOS, Son of sevenless. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 2 Key signal transduction mechanisms that operate in ASM to regulate migration. Migration is associated with activation of glycolipid-anchored receptor proteins (eg, uPAR, urokinase receptor) and cytokine receptors. The major pathway so far identified for ASM migration signals to p38 MAPK via PAK to culminate in HSP27 phosphorylation, which favors F-actin formation and cytoskeletal remodeling. Other events recently implicated in ASM migration include PI3K activation, possibly acting via Rho kinase (RhoK) and Rac1/Cdc42, and activation of ERK-dependent pathways. tPA, Tissue plasminogen activator. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 3 Airway epithelial and smooth muscle cell proliferation (A) and apoptosis (B) in vivo. PCNA immunoreactivity, and apoptosis detected by the TUNEL technique, were colocalized, respectively, with smooth muscle α-actin in illustrative airway sections of control rats. Note the dark gray to black stained nuclei indicating PCNA+ or apoptotic cells in the bundles of smooth muscle (closed arrows) and in the epithelium (open arrows). Scale bars, 20 μm. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 3 Airway epithelial and smooth muscle cell proliferation (A) and apoptosis (B) in vivo. PCNA immunoreactivity, and apoptosis detected by the TUNEL technique, were colocalized, respectively, with smooth muscle α-actin in illustrative airway sections of control rats. Note the dark gray to black stained nuclei indicating PCNA+ or apoptotic cells in the bundles of smooth muscle (closed arrows) and in the epithelium (open arrows). Scale bars, 20 μm. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 4 Hypothetical schema of the regulation of the ASM mass in asthmatic airways. LFA, Leukocyte function–associated antigen; VLA, very late activation antigen. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 5 β2-Agonists decrease activation of PI3K and ERK, whereas glucocorticoids (GCS) interfere with pathways leading to an increase in cyclin D1 message levels and prevent the GF-induced decline in cdk inhibitor (cdki) levels. GF, Growth factor; GSK, glycogen synthase kinase; PDE, phosphodiesterase; PKA, protein kinase A. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)

Fig 6 Interactions between glucocorticoids (GCS) and β2-agonists in ASM. GCS increase transcription of β2AR mRNA and diminish COX-2 induction, limiting the production of PGE2, which has opposing effects on cAMP: direct stimulation through specific prostaglandin EP2/EP4 receptors and indirect suppression through uncoupling of β2AR from adenylate cyclase (AC). GR, Glucocorticoid receptor; GRE, glucocorticoid response element. Journal of Allergy and Clinical Immunology 2004 114, S2-S17DOI: (10.1016/j.jaci.2004.04.039)