Bronchial Asthma Chronicpersistent Structural change Airway inflammation Airway Airway Hyperresponsiveness remodeling Pro-inflammatory cells Eosinophils Epithelial shedding T lymphocytes Smooth muscle Macrophages hypertrophy/hyperplasia Mast cells Mucus metaplasia Pro-inflammatory Subepithelial fibrosis mediators
Airway Remodeling Consequence of chronic airway inflammation May begin as early as 6 Epithelial shedding years old Smooth muscle hypertrophy/hyperplasia Refractory to recently Mucus metaplasia available anti-asthma Subepithelial fibrosis therapy
Smooth Muscle Hypretrophy/Hyperplasia 1.Increased rate of Mesenchymal cells division 2.Decreased rate of apoptosis 3.Migration Transformation Growth Factors Cytokine Contractile agonists through Reactive oxygen species G-protein coupled receptor Stretch stimulation Enzymes Extracellularmatrix
ASM T Cell Mitogens VLA-4 LFA-1 CD44 Contractile Growth Agonists Cell-Cell Factors Cytokines Interactions? GPCR ASM Cell PDGF IL-18 Histamine EGF TNF-d Endothelin-1 IGF-1,IGF-2 L-6 Thromboxane Leukotriene D
Ligands for the EGFR family Epidermal Growth Factor Receptor EGFR (EGFR) W/HER2) No high-affinity HB-EGF igand known Neuregulin 2 HB-EGE EGFR Epigen Tyrosine kinase Src PI3K Ras STAT3 Akt MAPK ERK p38 Pro- Cell Pro- survival Proliferation Apoptosis
EGFR upregulation on Asthma airways LEVEL OF EXPRESSION OF EGF RECEPTOR IMMUNOREACTIVITY Peripheral Large Bronchi Small Bronchi Arway Asthma Contrdl Asthma Control Asthma Control Asthma Control 58 6 1/8 4/7 48 67 Gland.positive/total Smooth muncle.positive/total 35 Control Asthma AM I RESPIR CRIT CARE MED 1998:157:1907-1912
EGFindependent proliferative pathway: GPCR transactivates EGFR GPCR Metallo- EGF-like ligands EGFR proteases >720 GPCRs >25 MMPs >13 EGFR agonists EGFR >29 ADAMs Erb82 ligand ErbB3 Erb84 LPA Thrombin Cell membrane 5 Up-regulation mRNA Intracellular signals cellular growth and tissue remodelling
Airway Smooth Muscle Cell Proliferation 口+20PD9w0 10 EGF B 144 RECF-R- ECFR一一一 AMLI, LTD4→Cys LTR→transactivation of EGFR→PI3K →ERK Respiratory Research 2006.7:42
Neutrophil elastase is mitogenic for ASM via ERK MAPK signaling pathway Elastase(0.5 ug/ml) C +anti-E +PD P-42/44 30 Through transactivation of EGFR By cleavage of ECF-like agonists (TGF-a and EGF) 05 Elastase(ug /mL) SB203580 P098059 Huang et al.,Life Sci.2004 ;74:2479-92
Airway Smooth Muscle Potential therapeutic targets: -EGFR -Tyrosine kinase -Common pathway ·PI3K ·ERK Refractory to corticosteroids